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PubMed: 14556719

Title
The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg.
Journal
Neuron
Volume
40
Issue
None
Pages
427-46
Date
2003-10-09
Authors
Brundin P | Ciechanover A

Evidence 7ee5b65614
JSON

An important player in the pathogenesis of PD is Parkin (PARK2))

p(HGNC:PRKN) positiveCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Parkinson Disease") positiveCorrelation p(HGNC:PRKN) View Subject | View Object

Appears in Networks:

Evidence dbfd08b0ae
JSON

If oligomerization of mutant Huntingtin is inhibited by administration of Congo red starting at this age, no aggregates can be detected in the brain 5weeks later (Sanchez et al., 2003).

a(CHEBI:"Congo Red") decreases a(HBP:"huntingtin aggregates") View Subject | View Object

Appears in Networks:

Evidence 34d70a233c
JSON

In a parallel experiment using a cell culture model, Congo red was found to increase proteasomal activity in cells expressing a polyglutamine protein but not in cells expressing a control protein (Sanchez et al., 2003).

a(CHEBI:"Congo Red") increases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence ba28a25cfc
JSON

Overexpression of Parkin can rescue cells from the UPR elicited by a variety of stresses, such as exposure to H2O2, DNA alkylating agents, short-wavelength UV light, high osmolarity, and heat shock (Imai et al., 2000)

a(CHEBI:"alkylating agent") increases bp(GO:"response to unfolded protein") View Subject | View Object

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a(CHEBI:"hydrogen peroxide") increases bp(GO:"response to unfolded protein") View Subject | View Object

Appears in Networks:

bp(GO:"response to unfolded protein") positiveCorrelation bp(MESH:"Osmolar Concentration") View Subject | View Object

Appears in Networks:

bp(MESH:"Heat-Shock Response") increases bp(GO:"response to unfolded protein") View Subject | View Object

Appears in Networks:

bp(MESH:"Osmolar Concentration") positiveCorrelation bp(GO:"response to unfolded protein") View Subject | View Object

Appears in Networks:

bp(MESH:"Ultraviolet Rays") increases bp(GO:"response to unfolded protein") View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) decreases bp(GO:"response to unfolded protein") View Subject | View Object

Appears in Networks:

Evidence 00a897038b
JSON

Concomitant cleavage of APP by beta and gamma secretase at specific sites can result in fragments (Abeta1-40 or Abeta1-42) that can misfold and form extracellular fibrils.

a(CHEBI:"amyloid-beta polypeptide 40") increases a(HBP:"amyloid-beta fibrils") View Subject | View Object

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a(CHEBI:"amyloid-beta polypeptide 42") increases a(HBP:"amyloid-beta fibrils") View Subject | View Object

Appears in Networks:

complex(GO:"gamma-secretase complex") increases rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta polypeptide 40"), a(CHEBI:"amyloid-beta polypeptide 42"))) View Subject | View Object

Appears in Networks:

p(HGNC:BACE1) increases rxn(reactants(p(HGNC:APP)), products(a(MESH:"Amyloid beta-Peptides"))) View Subject | View Object

Appears in Networks:

Evidence 1095df09a9
JSON

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game.

a(CHEBI:"amyloid-beta") association path(MESH:"Alzheimer Disease") View Subject | View Object

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bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(CHEBI:"amyloid-beta") View Subject | View Object

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path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

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Evidence 2143cf0fde
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However, Abeta has been demonstrated to reduce proteasome activity in reticulocyte lysates (Gregori et al., 1995), suggesting that increased levels of the peptide could underlie the reduction in UPS function observed in the AD brain.

a(CHEBI:"amyloid-beta") decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Reticulocytes

Evidence 4bef6b9daa
JSON

It has been shown that Abeta can be degraded by the proteasome in cultured neurons and astrocytes, and reatment with the proteasome inhibitor lactacystin decreased viability of cells exposed to Abeta (Lopez Salon et al., 2003).

a(CHEBI:lactacystin) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte
Cell Ontology (CL)
neuron

a(CHEBI:lactacystin) increases bp(GO:"cell death") View Subject | View Object

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Annotations
Cell Ontology (CL)
astrocyte
Cell Ontology (CL)
neuron

complex(GO:"proteasome complex") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte
Cell Ontology (CL)
neuron

Evidence 8af48b16b2
JSON

Finally, Synaptotagmin XI has also recently been reported to be a substrate of Parkin (Huynh et al., 2003). It is possible that ubiquitination of this substrate affects synaptic vesicle transport and/or transmitter release.

sec(a(CHEBI:neurotransmitter)) association p(HGNC:SYT11, pmod(Ub)) View Subject | View Object

Appears in Networks:

bp(GO:"synaptic vesicle transport") association p(HGNC:SYT11, pmod(Ub)) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) increases p(HGNC:SYT11, pmod(Ub)) View Subject | View Object

Appears in Networks:

p(HGNC:SYT11, pmod(Ub)) association bp(GO:"synaptic vesicle transport") View Subject | View Object

Appears in Networks:

p(HGNC:SYT11, pmod(Ub)) association sec(a(CHEBI:neurotransmitter)) View Subject | View Object

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Evidence 2312b4cbe2
JSON

Accumulation of ubiquitin conjugates and/or inclusion bodies associated with ubiquitin, proteasome, and certain disease-characteristic proteins have been reported in a broad array of chronic neurodegenerative diseases, such as the neurofibrillary tangles of Alzheimer’s disease (AD), brainstem Lewy bodies (LBs) (the neuropathological hallmark in Parkinson’s disease [PD]), Bunina bodies in Amyotrophic Lateral Sclerosis (ALS), and nuclear inclusions in CAG repeat expansion (polyglutamine/Q extension) disorders such as Huntington’s disease, Spinocerebellar Ataxias (SCAs), and Spinal and Bulbar Muscular Atrophy (SBMA; Kennedy’s disease) (reviewed recently by Alves-Rodrigues et al., 1998; Sherman and Goldberg, 2001) (Figure 2)

a(GO:"Bunina body") positiveCorrelation complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) View Subject | View Object

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a(GO:"Bunina body") positiveCorrelation complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) View Subject | View Object

Appears in Networks:

a(MESH:"Lewy Bodies") positiveCorrelation complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain Stem

a(MESH:"Lewy Bodies") positiveCorrelation complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain Stem

a(MESH:"Neurofibrillary Tangles") positiveCorrelation complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) View Subject | View Object

Appears in Networks:

a(MESH:"Neurofibrillary Tangles") positiveCorrelation complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) View Subject | View Object

Appears in Networks:

complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) positiveCorrelation a(MESH:"Neurofibrillary Tangles") View Subject | View Object

Appears in Networks:

complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) positiveCorrelation a(GO:"Bunina body") View Subject | View Object

Appears in Networks:

complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) positiveCorrelation path(MESH:"Huntington Disease") View Subject | View Object

Appears in Networks:

complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) positiveCorrelation path(MESH:"Spinocerebellar Ataxias") View Subject | View Object

Appears in Networks:

complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) positiveCorrelation path(MESH:"Bulbo-Spinal Atrophy, X-Linked") View Subject | View Object

Appears in Networks:

complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) positiveCorrelation a(MESH:"Lewy Bodies") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain Stem

complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) positiveCorrelation a(MESH:"Neurofibrillary Tangles") View Subject | View Object

Appears in Networks:

complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) positiveCorrelation a(GO:"Bunina body") View Subject | View Object

Appears in Networks:

complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) positiveCorrelation path(MESH:"Huntington Disease") View Subject | View Object

Appears in Networks:

complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) positiveCorrelation path(MESH:"Spinocerebellar Ataxias") View Subject | View Object

Appears in Networks:

complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) positiveCorrelation path(MESH:"Bulbo-Spinal Atrophy, X-Linked") View Subject | View Object

Appears in Networks:

complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) positiveCorrelation a(MESH:"Lewy Bodies") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain Stem

path(MESH:"Bulbo-Spinal Atrophy, X-Linked") positiveCorrelation complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) View Subject | View Object

Appears in Networks:

path(MESH:"Bulbo-Spinal Atrophy, X-Linked") positiveCorrelation complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) View Subject | View Object

Appears in Networks:

path(MESH:"Huntington Disease") positiveCorrelation complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) View Subject | View Object

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path(MESH:"Huntington Disease") positiveCorrelation complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) View Subject | View Object

Appears in Networks:

path(MESH:"Spinocerebellar Ataxias") positiveCorrelation complex(a(MESH:"Inclusion Bodies"), a(MESH:Ubiquitin)) View Subject | View Object

Appears in Networks:

path(MESH:"Spinocerebellar Ataxias") positiveCorrelation complex(a(GO:"proteasome complex"), a(MESH:"Inclusion Bodies")) View Subject | View Object

Appears in Networks:

Evidence c4ee53d230
JSON

Parkin has been reported also to associate with actin filaments but not with microtubules (Huynh et al., 2000).

p(HGNC:PRKN) association a(GO:"actin filament") View Subject | View Object

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a(GO:"actin filament") association p(HGNC:PRKN) View Subject | View Object

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Evidence 4660bcddab
JSON

In the vast majority of patients, some of the remaining nigral dopaminergic neurons exhibit aggregated proteins in the form of cytoplasmic LB inclusions

a(GO:"dopaminergic synapse") association a(MESH:"Lewy Bodies") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Pars Compacta
MeSH
Parkinson Disease

a(MESH:"Lewy Bodies") association a(GO:"dopaminergic synapse") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Pars Compacta
MeSH
Parkinson Disease

Evidence ca2c26afae
JSON

In contrast, the neurofibrillary tangles are intracellular and are rich in tau, a structural protein that is normally associated with microtubuli

a(GO:microtubule) association p(HGNC:MAPT) View Subject | View Object

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a(MESH:"Neurofibrillary Tangles") association p(HGNC:MAPT) View Subject | View Object

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p(HGNC:MAPT) association a(MESH:"Neurofibrillary Tangles") View Subject | View Object

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p(HGNC:MAPT) association a(GO:microtubule) View Subject | View Object

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Evidence 1c14b09c64
JSON

The protofibrils can further aggregate and precipitate as amyloid fibrils that are present in Lewy bodies, the hallmark of sporadic, late-onset PD

path(MESH:"Parkinson Disease") association a(MESH:"Lewy Bodies") View Subject | View Object

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a(HBP:"alpha-synuclein aggregates") association a(MESH:"Lewy Bodies") View Subject | View Object

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a(HBP:"alpha-synuclein fibrils") increases a(HBP:"alpha-synuclein aggregates") View Subject | View Object

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a(MESH:"Lewy Bodies") association a(HBP:"alpha-synuclein aggregates") View Subject | View Object

Appears in Networks:

a(MESH:"Lewy Bodies") association path(MESH:"Parkinson Disease") View Subject | View Object

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Evidence 3ea6fc23ba
JSON

AR-JP is characterized by lack of LBs and alphaSYN aggregates

a(HBP:"alpha-synuclein aggregates") positiveCorrelation path(MESH:"Parkinsonian Disorders") View Subject | View Object

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a(MESH:"Lewy Bodies") negativeCorrelation path(MESH:"Parkinsonian Disorders") View Subject | View Object

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path(MESH:"Parkinsonian Disorders") negativeCorrelation a(MESH:"Lewy Bodies") View Subject | View Object

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path(MESH:"Parkinsonian Disorders") positiveCorrelation a(HBP:"alpha-synuclein aggregates") View Subject | View Object

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Evidence baffa24dac
JSON

Thus, aggregation, which is the primary event, may lead to secondary damage by inhibiting the UPS (Bence et al., 2001).

a(HBP:"alpha-synuclein aggregates") decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

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Evidence ef9d279c7d
JSON

They present evidence that paired helical filaments obtained from AD brain or generated in vitro can inhibit proteasome function and that in AD brain tissue these filaments coimmunoprecipitate with the proteasome (Keck et al., 2003).

a(HBP:"paired helical filaments") decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence fbbf758dd5
JSON

Recent findings demonstrate that soluble aggregated proteins can inhibit the ubiquitin system (Bence et al., 2001)

a(HBP:"protein aggregates") decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

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Evidence 2c721306ab
JSON

Three different proteases, called alpha, beta, and gamma secretases, can cleave APP at specific sites and generate products that are well characterized.

a(MESH:"Amyloid Precursor Protein Secretases") increases rxn(reactants(p(HGNC:APP)), products(a(MESH:"Amyloid beta-Peptides"))) View Subject | View Object

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Evidence 3b2795549b
JSON

The plaques in AD are rich in amyloid beta peptides (Abeta) that are produced by proteolytic cleavage of the amyloid precursor peptide (APP), a glycolipid located in the outer cell membrane

a(MESH:"Amyloid beta-Peptides") association path(MESH:"Plaque, Amyloid") View Subject | View Object

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p(HGNC:APP) increases a(MESH:"Amyloid beta-Peptides") View Subject | View Object

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path(MESH:"Plaque, Amyloid") association a(MESH:"Amyloid beta-Peptides") View Subject | View Object

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Evidence 6c0e5be3d6
JSON

However, mice homozygous for both UCH-L1 and UCH-L3 deletions die early due to dysphagia and display degeneration of the nucleus tractus solitarius and area postrema in addition to the degeneration of the gracile tract that is observed in GAD mice that only have a UCH-L1 deletion

a(MESH:"Area Postrema") positiveCorrelation p(HGNC:UCHL1) View Subject | View Object

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a(MESH:"Area Postrema") positiveCorrelation p(HGNC:UCHL3) View Subject | View Object

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a(MESH:"Solitary Nucleus") positiveCorrelation p(HGNC:UCHL1) View Subject | View Object

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a(MESH:"Solitary Nucleus") positiveCorrelation p(HGNC:UCHL3) View Subject | View Object

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p(HGNC:UCHL1) decreases path(MESH:"Deglutition Disorders") View Subject | View Object

Appears in Networks:

p(HGNC:UCHL1) positiveCorrelation a(MESH:"Solitary Nucleus") View Subject | View Object

Appears in Networks:

p(HGNC:UCHL1) positiveCorrelation a(MESH:"Area Postrema") View Subject | View Object

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p(HGNC:UCHL3) decreases path(MESH:"Deglutition Disorders") View Subject | View Object

Appears in Networks:

p(HGNC:UCHL3) positiveCorrelation a(MESH:"Solitary Nucleus") View Subject | View Object

Appears in Networks:

p(HGNC:UCHL3) positiveCorrelation a(MESH:"Area Postrema") View Subject | View Object

Appears in Networks:

Evidence d407963904
JSON

The overriding hypothesis is that a defect in Parkin will result in accumulation of this protein(s), which is toxic to the dopaminergic neurons

a(MESH:"Dopaminergic Neurons") negativeCorrelation p(HGNC:PRKN) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) negativeCorrelation a(MESH:"Dopaminergic Neurons") View Subject | View Object

Appears in Networks:

p(HGNC:PRKN, var("?")) increases p(HGNC:PRKN) View Subject | View Object

Appears in Networks:

Evidence 56a320fd77
JSON

Since inclusion bodies are lacking in most cases of AR-JP, it is possible that the ubiquitination of Synphilin by wildtype Parkin plays a role in their formation, by targeting ubiquitinated Synphilin to these bodies and removing it from the cytosol where it can be toxic

a(MESH:"Inclusion Bodies") negativeCorrelation path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) increases p(HGNC:SNCAIP, pmod(Ub)) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) increases tloc(p(HGNC:SNCAIP, pmod(Ub)), fromLoc(GO:cytosol), toLoc(MESH:"Inclusion Bodies")) View Subject | View Object

Appears in Networks:

path(MESH:"Parkinsonian Disorders") negativeCorrelation a(MESH:"Inclusion Bodies") View Subject | View Object

Appears in Networks:

Evidence 25a0475584
JSON

In addition, other proteins, e.g., alphaSYN (Waelter et al., 2001) and the transcriptional cofactor CREB binding protein (CBP) (Jiang et al., 2003),colocalize with the protein inclusions

a(MESH:"Inclusion Bodies") association p(HGNC:SNCA) View Subject | View Object

Appears in Networks:

a(MESH:"Inclusion Bodies") association p(HGNC:CREBBP) View Subject | View Object

Appears in Networks:

p(HGNC:SNCA) association a(MESH:"Inclusion Bodies") View Subject | View Object

Appears in Networks:

p(HGNC:CREBBP) association a(MESH:"Inclusion Bodies") View Subject | View Object

Appears in Networks:

Evidence 22afca4cdf
JSON

Interestingly, with a few exceptions, AR-JP is characterized by a lack of LBs

a(MESH:"Lewy Bodies") negativeCorrelation path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:

path(MESH:"Parkinsonian Disorders") negativeCorrelation a(MESH:"Lewy Bodies") View Subject | View Object

Appears in Networks:

Evidence d0cad431f8
JSON

In conjunction with the formation of neurofibrillary tangles, the synthesis of the tau protein increases, and it undergoes an abnormal posttranslational modification characterized by hyperphosphorylation

a(MESH:"Neurofibrillary Tangles") increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

a(MESH:"Neurofibrillary Tangles") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

Evidence f249de0a16
JSON

For example, upregulation of the pathway is observed during massive degradation of skeletal muscle proteins that occurs under normal fasting but also under pathological conditions such as cancer-induced cachexia, severe sepsis, metabolic acidosis, or following denervation

a(MESH:Denervation) increases bp(GO:"protein catabolic process") View Subject | View Object

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Annotations
MeSH
Muscle, Skeletal

bp(GO:"protein catabolic process") increases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Muscle, Skeletal

path(MESH:Acidosis) increases bp(GO:"protein catabolic process") View Subject | View Object

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Annotations
MeSH
Muscle, Skeletal

path(MESH:Cachexia) increases bp(GO:"protein catabolic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Muscle, Skeletal

path(MESH:Sepsis) increases bp(GO:"protein catabolic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Muscle, Skeletal

Evidence a56eb5e830
JSON

This family of diseases is considered to be caused by a protein component of the proteinaceous infectious (prion) particles, originally proposed to be the causative agent of these diseases by Stanley Pruisner (1982).

a(MESH:Prions) increases path(MESH:"Prion Diseases") View Subject | View Object

Appears in Networks:

Evidence c52fbc2fc0
JSON

In cattle, prions can cause Bovine Spongiform Encephalopathy (BSE), called in lay terms “mad cow disease.”

a(MESH:Prions) increases path(MESH:"Encephalopathy, Bovine Spongiform") View Subject | View Object

Appears in Networks:

Evidence 0492162cd7
JSON

Initially, the ubiquitin-activating enzyme E1 activates ubiquitin in an ATP-requiring reaction to generate a high-energy thiol ester intermediate, E1-S~ubiquitin, where ubiquitin is bound to an internal E1 Cys residue

act(a(MESH:Ubiquitin)) increases complex(a(MESH:Ubiquitin), p(HGNC:UBA1)) View Subject | View Object

Appears in Networks:

composite(a(CHEBI:ATP), p(HGNC:UBA1)) increases act(a(MESH:Ubiquitin)) View Subject | View Object

Appears in Networks:

Evidence 270f55ed21
JSON

It should be noted that CFTR degradation is mediated by Endoplasmic Reticulum Associated Degradation (ERAD—a quality control mechanism that eliminates, via the UPS, misfolded/mutated/abnormal membrane or lumenal ER proteins following their retrotranslocation to the cytosol via the Sec61 translocation channel).

bp(GO:"ERAD pathway") regulates deg(p(HGNC:CFTR)) View Subject | View Object

Appears in Networks:

p(HGNC:SEC61A1) increases tloc(p(MESH:Proteins, pmod(HBP:misfolding)), fromLoc(GO:"endoplasmic reticulum lumen"), toLoc(GO:cytosol)) View Subject | View Object

Appears in Networks:

Evidence af56e030ce
JSON

Alternatively, if misfolded, it is believed to be directed to degradation via ERAD (Yedidia et al., 2001).

bp(GO:"ERAD pathway") increases deg(p(HGNC:PRNP, pmod(HBP:misfolding))) View Subject | View Object

Appears in Networks:

Evidence 6ec0d74b24
JSON

It then aggregates, and the insoluble protein elicits cell death via the Unfolded Protein Response (UPR).

bp(GO:"cell death") positiveCorrelation p(HGNC:GPR37) View Subject | View Object

Appears in Networks:

bp(GO:"response to unfolded protein") increases bp(GO:"cell death") View Subject | View Object

Appears in Networks:

p(HGNC:GPR37) positiveCorrelation bp(GO:"cell death") View Subject | View Object

Appears in Networks:

Evidence 3a845e7be8
JSON

Consistent with the notion that cyclin E is targeted by the Parkin ligase complex is the finding that Parkin deficiency leads to accumulation of cyclin E in cultured postmitotic neurons exposed to the glutamatergic excitotoxin kainite and promotes their apoptosis.

bp(GO:"neuron apoptotic process") positiveCorrelation p(HGNC:CCNE1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

composite(a(PUBCHEM:164810), p(HGNC:PRKN)) decreases p(HGNC:CCNE1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

p(HGNC:CCNE1) positiveCorrelation bp(GO:"neuron apoptotic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

Evidence 8292d96517
JSON

In PD, the main neuropathological feature is the progressive death of neurons in the substantia nigra pars compacta with resulting loss of dopaminergic innervation of the striatum.

bp(GO:"neuron death") positiveCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Pars Compacta

bp(GO:"synaptic transmission, dopaminergic") negativeCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Pars Compacta

path(MESH:"Parkinson Disease") positiveCorrelation bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Pars Compacta

path(MESH:"Parkinson Disease") negativeCorrelation bp(GO:"synaptic transmission, dopaminergic") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Pars Compacta

Evidence d8d0e86b44
JSON

Several apparently independent aberrations linked to defects in the UPS have been described in various rare forms of hereditary PD

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Parkinson Disease") negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 3258fd53d2
JSON

Miller and colleagues (Miller et al., 2003) have recently shown that this mutation destabilizes DJ-1 via promotion of its rapid, UPS-mediated degradation

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:PARK7)) View Subject | View Object

Appears in Networks:

p(HGNC:PARK7, var("p.Leu166Pro")) increases deg(p(HGNC:PARK7)) View Subject | View Object

Appears in Networks:

Evidence 33700ccf28
JSON

Recent work has highlighted a novel possible role for failure of the UPS in initiating prion disease, which can explain the cause of some cases of sporadic prion disease.

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(MESH:"Prion Diseases") View Subject | View Object

Appears in Networks:

path(MESH:"Prion Diseases") negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 7272fb75c0
JSON

The model proposed by Lindquist and collaborators is important as it identifies malfunction of UPS as a potentially important player in prion pathogenesis

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(MESH:"Prion Diseases") View Subject | View Object

Appears in Networks:

path(MESH:"Prion Diseases") negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 60afb5ed62
JSON

Lindquist and colleagues proposed that inhibition of UPS, which can be caused by ageing or following a pharmacological treatment, can lead to accumulation of PrPc in the cytoplasm where it is spontaneously converted into a PrPsc-like species because it is not rapidly degraded by the UPS (Hooper, 2003; Ma and Lindquist,2002;Ma et al., 2002).

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation bp(GO:aging) View Subject | View Object

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bp(GO:aging) negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

bp(GO:aging) increases p(HGNC:PRNP) View Subject | View Object

Appears in Networks:

Evidence c6ac390296
JSON

Once in the cytoplasm, the PrPc would be efficiently degraded by the UPS via the ERAD pathway, but this does not occur in the presence of the proteasome inhibitors

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:PRNP)) View Subject | View Object

Appears in Networks:

tloc(p(HGNC:PRNP), fromLoc(MESH:"Endoplasmic Reticulum"), toLoc(GO:cytosol)) increases deg(p(HGNC:PRNP)) View Subject | View Object

Appears in Networks:

Evidence 5f5c856ff4
JSON

The mutant SOD1 proteins, unlike the wild-type form, are degraded by the UPS (Hoffman et al., 1996;Johnston et al., 2000).

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:SOD1, var("?"))) View Subject | View Object

Appears in Networks:

Evidence 565f2c1861
JSON

Similarly, overexpression of the putative SOD1 E3 ligase dorfin can inhibit cell death induced by the mutant protein (Niwa et al., 2002), presumably by promoting its removal via the UPS.

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:SOD1, var("?"))) View Subject | View Object

Appears in Networks:

p(HGNC:SOD1, var("?")) increases bp(GO:"cell death") View Subject | View Object

Appears in Networks:

p(HGNC:RNF19A) decreases bp(GO:"cell death") View Subject | View Object

Appears in Networks:

p(HGNC:RNF19A) increases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence bef1f270dd
JSON

Urushitani and coworkers (Urushitani et al., 2002) showed that mutant SOD1 is degraded by the UPS in cultured cells and that oxidative damage increases the degree of ubiquitination of mutant but not of wild-type SOD1.

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:SOD1, var("?"))) View Subject | View Object

Appears in Networks:

bp(GO:"response to oxidative stress") increases p(HGNC:SOD1, pmod(Ub), var("?")) View Subject | View Object

Appears in Networks:

Evidence eac614c5c6
JSON

Consequently, the formation of aggregates may increase when the UPS fails

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") decreases a(HBP:"protein aggregates") View Subject | View Object

Appears in Networks:

Evidence 47b535fc71
JSON

This indicates that the truncated fragments are normally processed via the UPS, and therefore the disposal of fragments of mutant proteins will be impaired.

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:HTT, frag("?"))) View Subject | View Object

Appears in Networks:

Evidence 5314d44247
JSON

The degradation signal that is recognized by the 26S proteasome complex is made of a Lys48 polyubiquitin chain.

bp(GO:"protein K48-linked ubiquitination") increases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence 09eeb79010
JSON

Conjugation to other Lys residues, Lys63 for example, serves nonproteolytic functions of the system, such as activation of transcription

bp(GO:"protein K63-linked ubiquitination") increases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence 0566c6a9b7
JSON

In many of these cases, the modification leads to targeting of the tagged substrate for degradation in the lysosome/vacuole

bp(GO:"protein ubiquitination") increases bp(GO:"lysosomal protein catabolic process") View Subject | View Object

Appears in Networks:

bp(GO:"protein ubiquitination") increases bp(GO:"protein catabolic process in the vacuole") View Subject | View Object

Appears in Networks:

Evidence c3a3e99d72
JSON

The UPS can be regulated at the level of ubiquitination or at the level of proteasome activity

bp(GO:"protein ubiquitination") regulates bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

complex(GO:"proteasome complex") regulates bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence f780fa3eea
JSON

Consequently, due to the increased stress, mutant SOD1 will misfold more rapidly

bp(GO:"response to oxidative stress") increases p(HGNC:SOD1, pmod(HBP:misfolding), var("?")) View Subject | View Object

Appears in Networks:

Evidence feef7fd40f
JSON

The UPR is a mechanism that involves a stress response in the ER, including increased biosynthesis of ER chaperones, in response to accumulation of misfolded/denatured/mutated proteins in this organelle (for a recent review on UPR, see Kaufman, 2002).

bp(GO:"response to unfolded protein") increases bp(GO:"response to endoplasmic reticulum stress") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endoplasmic Reticulum

bp(GO:"response to unfolded protein") increases a(MESH:"Molecular Chaperones") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endoplasmic Reticulum

p(MESH:Proteins, pmod(HBP:misfolding)) increases bp(GO:"response to unfolded protein") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endoplasmic Reticulum

p(MESH:Proteins, var("?")) increases bp(GO:"response to unfolded protein") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endoplasmic Reticulum

Evidence 23dec23851
JSON

Ubiquitin-mediated proteolysis of a variety of cellular proteins plays an important role in many basic cellular processes. Among these are regulation of cell cycle and division, differentiation and development, involvement in the cellular response to stress and extracellular effectors, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels and the secretory pathway, DNA repair, transcriptional regulation, transcriptional silencing, long-term memory, circadian rhythms, regulation of the immune and inflammatory responses,and biogenesis of organelles

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"cell cycle") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"cell division") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"cell differentiation") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(MESH:"Cell Proliferation") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"cellular response to stress") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates a(MESH:"Receptors, Cell Surface") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates a(MESH:"Ion Channels") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(MESH:"Secretory Pathway") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"DNA repair") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"gene silencing") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"long-term memory") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"circadian rhythm") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"immune response") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:

bp(GO:"ubiquitin-dependent protein catabolic process") regulates bp(GO:"organelle organization") View Subject | View Object

Appears in Networks:

Evidence 88b900d936
JSON

The proteasome activity in the mammalian brain decreases with increasing age (Keller et al., 2002), suggesting that the aged brain is less able to handle the aberrantly folded Abeta

bp(GO:aging) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

act(complex(GO:"proteasome complex")) negativeCorrelation bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 0938de507b
JSON

It appears that E3s play a key role in the ubiquitin-mediated proteolytic cascade since they serve as the specific substrate recognition factors of the system

bp(GO:proteolysis) association p(HGNC:UBA3) View Subject | View Object

Appears in Networks:

p(HGNC:UBA3) association bp(GO:proteolysis) View Subject | View Object

Appears in Networks:

Evidence dd58639d16
JSON

Wild-type alphaSYN is monomeric, but at high concentration, it oligomerizes to beta-pleated sheets known as protofibrils

bp(HBP:"Alpha-synuclein Oligomerization") positiveCorrelation p(HGNC:SNCA) View Subject | View Object

Appears in Networks:

bp(HBP:"Alpha-synuclein Oligomerization") increases a(HBP:"alpha-synuclein fibrils") View Subject | View Object

Appears in Networks:

p(HGNC:SNCA) positiveCorrelation bp(HBP:"Alpha-synuclein Oligomerization") View Subject | View Object

Appears in Networks:

Evidence ee1383d275
JSON

On the other hand, Parkin appears to have a role in synaptic transmission that has not been described previously and that was not possible to observe in patients.

bp(MESH:"Synaptic Transmission") association p(HGNC:PRKN) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) association bp(MESH:"Synaptic Transmission") View Subject | View Object

Appears in Networks:

Evidence 9713594572
JSON

A rather surprising, recently discovered substrate of Parkin is cyclin E (Staropoli et al., 2003) that is ubiquitinated by the SCF complex that contains Parkin.

complex(GO:"SCF ubiquitin ligase complex") increases p(HGNC:CCNE1, pmod(Ub)) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) association p(HGNC:CCNE1) View Subject | View Object

Appears in Networks:

p(HGNC:CCNE1) association p(HGNC:PRKN) View Subject | View Object

Appears in Networks:

Evidence 38a293d898
JSON

Finally, some patients express mutant presenilin proteins 1 and 2 (PS1 and PS2) that can change the processing of APP by altering gamma secretase activity, thereby promoting the generation of amyloidogenic Abeta (Hardy and Selkoe, 2002).

act(complex(GO:"gamma-secretase complex")) association p(HGNC:PSEN1, var("?")) View Subject | View Object

Appears in Networks:

act(complex(GO:"gamma-secretase complex")) association p(HGNC:PSEN2, var("?")) View Subject | View Object

Appears in Networks:

p(HGNC:PSEN1, var("?")) association act(complex(GO:"gamma-secretase complex")) View Subject | View Object

Appears in Networks:

p(HGNC:PSEN1, var("?")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

p(HGNC:PSEN2, var("?")) association act(complex(GO:"gamma-secretase complex")) View Subject | View Object

Appears in Networks:

p(HGNC:PSEN2, var("?")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

Evidence df98747608
JSON

Degradation of polyubiquitinated substrates is carried out by a large protease complex, the 26S proteasome that does not generally recognize nonmodified substrates

complex(GO:"proteasome complex") increases deg(p(MESH:Proteins, pmod(GO:"protein K48-linked ubiquitination"))) View Subject | View Object

Appears in Networks:

complex(GO:"proteasome complex") increases deg(p(MESH:Proteins, pmod(GO:"protein K63-linked ubiquitination"))) View Subject | View Object

Appears in Networks:

Evidence e6522ac74b
JSON

In one established and exceptional case, however that of the polyamine synthesizing enzyme ornithine decarboxylase (ODC), the proteasome recognizes and degrades the substrate following its association with another protein, antizyme, without prior ubiquitination

complex(GO:"proteasome complex") increases deg(complex(p(HGNC:OAZ1), p(HGNC:ODC1))) View Subject | View Object

Appears in Networks:

Evidence 65979e8f99
JSON

The proteasome is a large, multicatalytic protease that degrades polyubiquitinated proteins to small peptides

complex(GO:"proteasome complex") increases a(CHEBI:peptide) View Subject | View Object

Appears in Networks:

Evidence 74c542809a
JSON

They found that the proteasome catalytic activity was decreased in neuroblastoma cells following 1 week of expression of a mutant SOD1 gene.

act(complex(GO:"proteasome complex")) negativeCorrelation p(HGNC:SOD1, var("?")) View Subject | View Object

Appears in Networks:

p(HGNC:SOD1, var("?")) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence 585e009b2f
JSON

Neuronal autophagy has been found to occur following chronic, low-grade proteasomal inhibition in cultured neuroblastoma cells (Ding et al., 2003) and may reflect activation of the lysosomal system as cells try to protect themselves during stress (Larsen and Sulzer, 2002).

act(complex(GO:"proteasome complex")) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

Evidence 5d6303efa9
JSON

Lunkes and colleagues demonstrated that truncated Huntingtin, which has undergone proteolytic cleavage in the cytoplasm, accumulates more rapidly if the proteasome is pharmacologically inhibited (Lunkes et al., 2002).

act(complex(GO:"proteasome complex")) decreases p(HGNC:HTT, frag("?")) View Subject | View Object

Appears in Networks:

Evidence 662dc8809b
JSON

Also, since a folded protein would not be able to fit through the narrow proteasomal channel, it is assumed that the 19S particle unfolds substrates and inserts them into the 20S CP

complex(GO:"proteasome regulatory particle") increases bp(GO:"protein unfolding") View Subject | View Object

Appears in Networks:

Evidence 752502934d
JSON

PrPc is abundant in many cells throughout the body, particularly in the immune and nervous systems, and is typically anchored to the outer cell membrane, where it may act as a copper binding protein with antioxidant properties (Brown,2002).

p(HGNC:PRNP) increases complex(a(CHEBI:"copper(2+)"), p(HGNC:PRNP)) View Subject | View Object

Appears in Networks:

Evidence c9fc3f70ad
JSON

One of several E2 enzymes (ubiquitin-carrier proteins or Ubiquitin-Conjugating enzymes [UBCs]) transfers the activated ubiquitin moiety from E1, via an additional high-energy thiol ester intermediate, E2-S~ubiquitin, to the substrate that is specifically bound to an E3, a member of the ubiquitinprotein ligase family of proteins

p(HGNC:UBA2) decreases complex(a(MESH:Ubiquitin), p(HGNC:UBA1)) View Subject | View Object

Appears in Networks:

p(HGNC:UBA2) increases complex(a(MESH:Ubiquitin), p(HGNC:UBA3)) View Subject | View Object

Appears in Networks:

Evidence 8dcc2000cb
JSON

For the Homologous to the E6-AP C Terminus (HECT) domain E3s, the ubiquitin is transferred once again from the E2 enzyme to an active site Cys residue on the E3 to generate a third high-energy thiol ester intermediate, ubiquitin-S~E3, prior to its transfer to the ligase bound substrate

p(HGNC:UBA2) increases complex(a(MESH:Ubiquitin), p(INTERPRO:"HECT domain")) View Subject | View Object

Appears in Networks:

Evidence d6d0335618
JSON

Finally, there is also evidence for a reduced activity of E1 and E2 enzymes in cerebral cortex samples from AD patients compared to age-matched controls (Lopez Salon et al., 2000).

act(p(HGNC:UBA2)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

act(p(HGNC:UBA1)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:UBA1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:UBA2)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence e812aafcda
JSON

Thus,Huntingtin was found to be ubiquitinated and also to interact with E2-25 kDa (Kalchman et al., 1996).

p(HGNC:HTT) increases complex(p(HGNC:HTT), p(HGNC:UBA2)) View Subject | View Object

Appears in Networks:

p(HGNC:UBA2) increases p(HGNC:HTT, pmod(Ub)) View Subject | View Object

Appears in Networks:

Evidence f30764c429
JSON

Interestingly, mutation at R42 abrogates the binding of Parkin to the proteasome, suggesting that it can cause AR-JP.

complex(a(GO:"proteasome complex"), p(HGNC:PRKN)) decreases path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:

p(HGNC:PRKN, var("p.Arg42")) decreases complex(a(GO:"proteasome complex"), p(HGNC:PRKN)) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN, var("p.Arg42")) increases path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:

Evidence c6bd2fa2fd
JSON

Indeed, it has been reported that Parkin associates with the RPN10 (S5a) subunit of the 26S proteasome (Sakata et al., 2003)

p(HGNC:PRKN) association p(HGNC:PSMD4) View Subject | View Object

Appears in Networks:

p(HGNC:PSMD4) association p(HGNC:PRKN) View Subject | View Object

Appears in Networks:

Evidence 8fdf01bbd5
JSON

One of these substrates is Cell Division Control related protein (CDCrel-1) (Zhang et al., 2000), an ~44kDa member of the septin family of proteins that includes GTPases required for cytokinesis

p(HGNC:PRKN) increases p(HGNC:SEPT5, pmod(Ub)) View Subject | View Object

Appears in Networks:

Evidence 379010e5f5
JSON

A second important substrate of Parkin is the Parkin-associated endothelial-like (Pael) receptor, a putative G protein-coupled transmembrane polypeptide (Imai et al., 2001). When overexpressed in cells, the receptor becomes misfolded

p(HGNC:PRKN) association p(HGNC:GPR37) View Subject | View Object

Appears in Networks:

p(HGNC:GPR37) increases p(HGNC:GPR37, pmod(HBP:misfolding)) View Subject | View Object

Appears in Networks:

p(HGNC:GPR37) association p(HGNC:PRKN) View Subject | View Object

Appears in Networks:

Evidence 31b6d20d03
JSON

Of note is that overexpression of Parkin also suppresses alpha-synuclein (alphSYN) toxicity, suggesting that Parkin may play a role in regulating this protein as well (see below)

p(HGNC:PRKN) decreases act(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) regulates p(HGNC:SNCA) View Subject | View Object

Appears in Networks:

Evidence 790b0fb965
JSON

Another substrate of Parkin is a novel 22 kDa form of O-glycosylated SYN (Sp22) (Shimura et al., 2001)

p(HGNC:PRKN) association p(HGNC:SNCA, pmod(OGlyco)) View Subject | View Object

Appears in Networks:

p(HGNC:SNCA, pmod(OGlyco)) association p(HGNC:PRKN) View Subject | View Object

Appears in Networks:

Evidence 536e435a3e
JSON

Parkin also ubiquitinates Synphilin-1, a protein of hitherto unknown function that contains a coiled-coiled domain and an ATP/GTP binding motif and that associates with alphaSYN (Chung et al., 2001).

p(HGNC:PRKN) increases p(HGNC:SNCAIP, pmod(Ub)) View Subject | View Object

Appears in Networks:

p(HGNC:SNCA) association p(HGNC:SNCAIP) View Subject | View Object

Appears in Networks:

p(HGNC:SNCAIP) association p(HGNC:SNCA) View Subject | View Object

Appears in Networks:

Evidence 321d109e02
JSON

Concomitantly, it reduced the inhibition of the proteasome and the activation of caspase 12 that are induced by accumulation of the polyglutamine-containing fragment

p(HGNC:PRKN) increases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) decreases act(p(HGNC:CASP12)) View Subject | View Object

Appears in Networks:

p(HGNC:ATXN3, frag("?")) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

p(HGNC:ATXN3, frag("?")) increases act(p(HGNC:CASP12)) View Subject | View Object

Appears in Networks:

Evidence a8024297a4
JSON

Overexpression of Parkin is reported to attenuate cyclin E accumulation and rescue the cells from apoptosis

p(HGNC:PRKN) decreases p(HGNC:CCNE1) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) decreases bp(GO:"neuron apoptotic process") View Subject | View Object

Appears in Networks:

Evidence e29a6ab50f
JSON

In the dopamine-producing neuroblastoma cell line SH-SY5Y, Parkin rescued the cells from p38-induced cell death

p(HGNC:AIMP2) increases bp(GO:"cell death") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

p(HGNC:PRKN) decreases bp(GO:"cell death") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence 195ba7f6bb
JSON

Yet, it is possible that the ligase regulates actin activity by ubiquitinating an actin-associated protein, which in turn affects the function of actin and thereby influences the movement of synaptic vesicles

p(HGNC:PRKN) regulates act(a(MESH:Actins)) View Subject | View Object

Appears in Networks:

Evidence af1decb255
JSON

The suggestion that the glycosylated form of alphaSYN is targeted by Parkin (Shimura et al., 2001) may resolve part of the enigma

p(HGNC:PRKN) association p(HGNC:SNCA, pmod(Glyco)) View Subject | View Object

Appears in Networks:

p(HGNC:SNCA, pmod(Glyco)) association p(HGNC:PRKN) View Subject | View Object

Appears in Networks:

Evidence 168c955bf2
JSON

An important finding, however, in that respect is that aggregated and even monomeric alphaSYN bind to the S6' proteasome subunit and inhibit proteasomal function (Snyder et al., 2003).

complex(a(HBP:"alpha-synuclein aggregates"), p(HGNC:PSMC4)) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PSMC4), p(HGNC:SNCA)) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence 2621089c91
JSON

The stability of additional proteins depends on association with ancillary proteins, such as molecular chaperones, that act as recognition elements in trans and serve as a link to the appropriate ligase.

complex(a(MESH:"Molecular Chaperones"), a(MESH:Proteins)) increases bp(GO:"protein stabilization") View Subject | View Object

Appears in Networks:

Evidence 63f4bfb4cb
JSON

Following degradation of the substrate, short peptides are released along with free and reusable ubiquitin.

deg(complex(a(MESH:Proteins), a(MESH:Ubiquitin))) increases a(MESH:Ubiquitin) View Subject | View Object

Appears in Networks:

deg(complex(a(MESH:Proteins), a(MESH:Ubiquitin))) increases a(CHEBI:peptide) View Subject | View Object

Appears in Networks:

Evidence 9b000e558a
JSON

E3s catalyze the last step in the conjugation process: covalent attachment of ubiquitin to the substrate.

p(HGNC:UBA3) increases bp(GO:"protein ubiquitination") View Subject | View Object

Appears in Networks:

Evidence 73e72bccdc
JSON

In some other cases, the first ubiquitin moiety is conjugated to the substrate by one E3, while chain elongation is catalyzed by a different ligase, often termed E4

p(HGNC:UBA3) increases bp(GO:"protein ubiquitination") View Subject | View Object

Appears in Networks:

p(HGNC:MOCS3) increases bp(GO:"protein polyubiquitination") View Subject | View Object

Appears in Networks:

Evidence b143923c9a
JSON

Two ubiquitin binding subunits of the 19S RP have been identified, Rpn10 (S5a in mammalian cells) and Rpt5 (S6'); however, their essential role and mode of action have not been discerned

p(HGNC:PSMC3) increases complex(a(MESH:Ubiquitin), p(HGNC:PSMC3)) View Subject | View Object

Appears in Networks:

p(HGNC:PSMD4) increases complex(a(MESH:Ubiquitin), p(HGNC:PSMD4)) View Subject | View Object

Appears in Networks:

Evidence 23cf26fafa
JSON

It interacts with the human homolog of Rad23, a cytosolic protein that binds polyubiquitinated proteins and is involved, most probably, in shuttling them to the proteasome.

p(HGNC:ATXN3) increases complex(p(HGNC:ATXN3), p(HGNC:RAD23A)) View Subject | View Object

Appears in Networks:

p(HGNC:RAD23A) increases tloc(p(HGNC:ATXN3, pmod(Ub)), fromLoc(GO:cytosol), toLoc(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence 6300a62586
JSON

The Prion protein normally interacts with the chaperone BiP and undergoes assisted folding (Jin et al., 2000).

complex(p(HGNC:HSPA5), p(HGNC:PRNP)) increases bp(GO:"protein folding") View Subject | View Object

Appears in Networks:

Evidence 7062bd6ec1
JSON

In a cell culture model, they overexpressed mutant Huntingtin and observed proteasomal inhibition accompanied by cell cycle arrest

p(HGNC:HTT) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

p(HGNC:HTT) increases bp(GO:"cell cycle arrest") View Subject | View Object

Appears in Networks:

Evidence 6d8b44ba93
JSON

DJ-1 activity may be regulated by SUMOylation, as it was found that it binds to the SUMO E3 PIASx (Takahashi et al., 2001).

complex(p(HGNC:PARK7), p(HGNC:PIAS2)) increases p(HGNC:PARK7, pmod(Sumo)) View Subject | View Object

Appears in Networks:

p(HGNC:PARK7, pmod(Sumo)) regulates act(p(HGNC:PARK7)) View Subject | View Object

Appears in Networks:

Evidence 24cd81c3b5
JSON

Such a partner can be, for example, the cochaperone CHIP (Carboxy terminus of the Hsc70-Interacting Protein) that was found to increase the activity of Parkin, possibly by acting as an E4 (Imai et al., 2002) or the proteasome (see above).

complex(p(HGNC:PRKN), p(HGNC:STUB1)) increases act(p(HGNC:PRKN)) View Subject | View Object

Appears in Networks:

Evidence 5ec25cc1ce
JSON

alphaSYN is a small, 140 amino acid residue protein that is thought to regulate/participate in dopamine neurotransmission/release via effects on vesicular storage

p(HGNC:SNCA) regulates bp(GO:"dopamine secretion, neurotransmission") View Subject | View Object

Appears in Networks:

p(HGNC:SNCA) regulates bp(GO:"dopamine secretion") View Subject | View Object

Appears in Networks:

Evidence 2f9f84080d
JSON

Overexpression of wild-type, but in particular mutant alphaSYN in many cell types but not in all, induces apoptosis or sensitizes the cells to toxic agents, including proteasome inhibitors (see, for example, Lee et al.,2001a).

p(HGNC:SNCA) increases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:

p(HGNC:SNCA, var("?")) increases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:

Evidence bc8178185f
JSON

Instead, impairment of alphaSYN function may disturb ubiquitination of alphaSYN-associated proteins, such as Synphilin (Chung et al., 2001) and tyrosine hydroxylase (Doskeland and Flatmark, 2002), and thereby perturb neuronal homeostasis

act(p(HGNC:SNCA)) increases p(HGNC:SNCAIP, pmod(Ub)) View Subject | View Object

Appears in Networks:

act(p(HGNC:SNCA)) increases p(HGNC:TH, pmod(Ub)) View Subject | View Object

Appears in Networks:

act(p(HGNC:SNCA)) regulates bp(GO:"homeostatic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

Evidence e0ea7f09b9
JSON

CDCrel-1 has been implicated in the inhibition of exocytosis through its interactions with syntaxin

complex(p(HGNC:SEPT5), p(HGNC:STX1A)) decreases bp(GO:exocytosis) View Subject | View Object

Appears in Networks:

Evidence 08e7ade79d
JSON

Following transfection to a cell line, wild-type CDCrel-1 inhibits secretion of growth hormone, while the dominant-negative species increases secretion (Beites et al., 1999

p(HGNC:SEPT5) decreases sec(a(CHEBI:"growth hormone")) View Subject | View Object

Appears in Networks:

Evidence 147943b3ef
JSON

It is possible that CDCrel-1 is involved in regulating transmitter release via its role in regulating synaptic vesicle dynamics, and its accumulation in patients with a mutation in Parkin perturbs the process.

p(HGNC:SEPT5) regulates sec(a(CHEBI:neurotransmitter)) View Subject | View Object

Appears in Networks:

p(HGNC:SEPT5) regulates act(a(GO:"synaptic vesicle")) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN, var("?")) decreases act(p(HGNC:SEPT5)) View Subject | View Object

Appears in Networks:

Evidence 35d434e27c
JSON

It has been reported recently that while the monomeric form of UCH-L1 catalyzes deubiquitination, the dimers display a ubiquitin ligase activity that generates ubiquitin-K63 bonds (Liu et al., 2002).

complex(p(HGNC:UCHL1), p(HGNC:UCHL1)) increases bp(GO:"protein K63-linked ubiquitination") View Subject | View Object

Appears in Networks:

p(HGNC:UCHL1) decreases bp(GO:"protein ubiquitination") View Subject | View Object

Appears in Networks:

Evidence 656f12255e
JSON

Mono- and diubiquitinated alphaSYN were polyubiquitinated by the enzyme, suggesting that it acts as an E4 (Koegl et al., 1999)

p(HGNC:UCHL1) increases p(HGNC:SNCA, pmod(Ub)) View Subject | View Object

Appears in Networks:

Evidence 90bf25d564
JSON

Mutant tau alone does not cause AD, favoring the idea that accumulation of erroneously processed Abeta is a key event in AD pathogenesis

composite(a(CHEBI:"amyloid-beta"), p(HGNC:MAPT, var("?"))) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

Evidence 540be357e3
JSON

Proteolytic processing/degradation of tau is also believed to be important for the formation of the neurofibrillary tangles,although the molecular pathways involved in this process are not fully understood

deg(p(HGNC:MAPT)) increases a(MESH:"Neurofibrillary Tangles") View Subject | View Object

Appears in Networks:

Evidence 82d719e41a
JSON

Administration of cystamine, a transglutaminase inhibitor, can reduce aggregate formation and death in cells expressing atrophin-1 (DRPLA model) (Igarashi et al., 1998) and in cells expressing mutant androgen receptor (SBMA model) (Mandrusiak et al., 2003).

composite(a(CHEBI:cystamine), p(HGNC:AR, var("?"))) decreases a(HBP:"protein aggregates") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:cystamine), p(HGNC:AR, var("?"))) decreases bp(GO:"cell death") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:cystamine), p(HGNC:ATN1)) decreases a(HBP:"protein aggregates") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:cystamine), p(HGNC:ATN1)) decreases bp(GO:"cell death") View Subject | View Object

Appears in Networks:

Evidence 86e60419f9
JSON

Thus, exposure to lactacystin resulted in increased cell death in human cell lines expressing mutant SOD1 (Aquilano et al., 2003; Hyun et al., 2003).

composite(a(CHEBI:lactacystin), p(HGNC:SOD1, var("?"))) increases bp(GO:"cell death") View Subject | View Object

Appears in Networks:

Evidence f8ce284b30
JSON

There is very little evidence to suggest that alterations in SOD are a common feature of sporadic ALS (Alexander et al., 2002).

p(HGNC:SOD1, var("?")) association path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") association p(HGNC:SOD1, var("?")) View Subject | View Object

Appears in Networks:

Evidence 54d105f14d
JSON

The first is that the mutant protein promotes oxidative stress through a gain-of-function mechanism where improper handling of copper may lead to the enzyme catalyzing aberrant pro-oxidant reactions (Cleveland and Liu, 2000).

p(HGNC:SOD1, var("?")) increases bp(GO:"response to oxidative stress") View Subject | View Object

Appears in Networks:

Evidence 29eb009f7a
JSON

In the other model, the expression of mutant SOD1 alone was sufficient to induce oxidative stress, giving rise to increased proteasome activity, possibly due to the need to remove oxidatively damaged proteins (Hyun et al., 2003).

p(HGNC:SOD1, var("?")) increases bp(GO:"response to oxidative stress") View Subject | View Object

Appears in Networks:

p(HGNC:SOD1, var("?")) increases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence a58fa8c137
JSON

The normal function of SOD1 is to scavenge oxygen radicals and prevent oxidative stress.

p(HGNC:SOD1) decreases bp(GO:"response to oxidative stress") View Subject | View Object

Appears in Networks:

Evidence c61c99cd67
JSON

Parkin ubiquitinates and promotes the degradation of the insoluble Pael receptor, acting in this reaction along Ubc6 and Ubc7, two E2s located in the ER

composite(p(HGNC:PRKN), p(HGNC:UBE2G1), p(HGNC:UBE2J1)) increases deg(p(HGNC:GPR37)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endoplasmic Reticulum

Evidence 203c683ec1
JSON

Overexpression of Synphilin-1 with alphaSYN results in the formation of protein inclusions, yet the function of Synphilin in this process as well as the role of its ubiquitination are still elusive

composite(p(HGNC:SNCA), p(HGNC:SNCAIP)) increases a(MESH:"Inclusion Bodies") View Subject | View Object

Appears in Networks:

Evidence 00b51b285b
JSON

Mutations in the tau gene can cause the tauopathy Pick’s disease (mentioned above).

g(HGNC:MAPT, var("?")) increases path(MESH:"Pick Disease of the Brain") View Subject | View Object

Appears in Networks:

Evidence 56be8aeea6
JSON

Recently discovered mutations in the DJ-1 gene have also been associated with AR-JP (Bonifati et al., 2003).

g(HGNC:PARK7, var("?")) association path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:

path(MESH:"Parkinsonian Disorders") association g(HGNC:PARK7, var("?")) View Subject | View Object

Appears in Networks:

Evidence af3fffec3b
JSON

The affinity of the polyglutamine fragment to Parkin was increased by Hsp70, in agreement with the hypothesis that molecular chaperones may play a role in the recruitment of misfolded proteins to the conjugation machinery (see, for example, Bercovich et al., 1997).

p(FPLX:HSPA) increases complex(p(HGNC:ATXN3, frag("?")), p(HGNC:PRKN)) View Subject | View Object

Appears in Networks:

Evidence 302596ea7f
JSON

Overexpression of the chaperone HSP70 has been found to reduce aggregate formation and death in nonneuronal cultured cells expressing mutant SOD1 (Bruening et al.,1999).

p(FPLX:HSPA) increases a(HBP:"protein aggregates") View Subject | View Object

Appears in Networks:

p(FPLX:HSPA) increases bp(GO:"cell death") View Subject | View Object

Appears in Networks:

Evidence 3a98c4d7b1
JSON

They have demonstrated that AD can be caused by mutations in the APP gene, either in the vicinity of the secretase cleavage sites, causing abnormal APP processing, or in the sequence coding for Abeta, giving rise to a peptide that is more likely to self-aggregate

p(HGNC:APP, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:APP, var("?")) increases a(HBP:"amyloid-beta aggregates") View Subject | View Object

Appears in Networks:

Evidence a922b85444
JSON

Tentative support for this idea was obtained in a cell model of HD, where expression of a dominant-negative variant of the E2 Cdc34p decreased the formation of intranuclear inclusions but increased the likelihood of cell death (Saudou et al., 1998).

p(HGNC:CDC34, var("?")) decreases a(MESH:"Inclusion Bodies") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Huntington Disease

p(HGNC:CDC34, var("?")) increases bp(GO:"cell death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Huntington Disease

Evidence 10c5a8ada3
JSON

This case may be analogous to the loss of function observed during the rapid degradation of mutated ΔF508 Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which is also an active protein, and that the rapid degradation of which contributes to the pathogenesis of cystic fibrosis (CF) in patients carrying the mutation

p(HGNC:CFTR, var("p.Phe508del")) increases deg(p(HGNC:CFTR)) View Subject | View Object

Appears in Networks:

p(HGNC:CFTR, var("p.Phe508del")) increases path(MESH:"Cystic Fibrosis") View Subject | View Object

Appears in Networks:

Evidence 826af9c02f
JSON

Importantly, the insoluble Pael receptor accumulates in the brains of patients with AR-JP

p(HGNC:GPR37) positiveCorrelation path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Parkinsonian Disorders") positiveCorrelation p(HGNC:GPR37) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 54a1a554ea
JSON

The disease is caused by a mutation in the gene coding for Huntingtin—a protein of hitherto unknown function, although it has been recently implicated in the control of gene transcription (Zuccato et al., 2003).

p(HGNC:HTT, var("?")) increases path(MESH:"Huntington Disease") View Subject | View Object

Appears in Networks:

Evidence 08dfe3857b
JSON

However, a contribution to the pathogenesis by loss of function of Huntingtin encoded from the wild-type allele has not been excluded in HD (Cattaneo et al., 2001), since the mutant protein not only aggregates itself but can also promote aggregation of the wild-type protein (Busch et al.,2003).

p(HGNC:HTT, var("?")) increases a(HBP:"huntingtin aggregates") View Subject | View Object

Appears in Networks:

Evidence b8a9ea97eb
JSON

Another study has also demonstrated that UPS inhibition is only revealed under conditions of increased stress in cells expressing mutant Huntingtin (Ding et al., 2002)

p(HGNC:HTT, var("?")) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 358eb7c400
JSON

A study in cultured mouse neuroblastoma cells showed that N-terminal mutant Huntingtin inhibited the 20S proteasome catalytic activity, in turn causing impaired proteasomal degradation of p53, subsequent loss of mitochondrial membrane potential, release of cytochrome c, caspase activation, and apoptosis (Jana et al., 2001) (Figure 2).

p(HGNC:HTT, var("?")) decreases act(p(HBP:"20 S Proteasome")) View Subject | View Object

Appears in Networks:

p(HGNC:HTT, var("?")) decreases deg(p(HGNC:TP53)) View Subject | View Object

Appears in Networks:

p(HGNC:HTT, var("?")) decreases bp(MESH:"Membrane Potential, Mitochondrial") View Subject | View Object

Appears in Networks:

p(HGNC:HTT, var("?")) increases sec(a(CHEBI:"cytochrome c")) View Subject | View Object

Appears in Networks:

p(HGNC:HTT, var("?")) increases act(p(FPLX:Caspase)) View Subject | View Object

Appears in Networks:

p(HGNC:HTT, var("?")) increases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:

Evidence 6475640f8b
JSON

For example, modification of the Cullin component of the SCF E3 complexes by the ubiquitin-like protein NEDD8 increases the affinity of the ligases to the E2 component of the conjugation machinery

p(HGNC:NEDD8) increases complex(a(GO:"SCF ubiquitin ligase complex"), p(HGNC:UBA2)) View Subject | View Object

Appears in Networks:

Evidence 165bf8958f
JSON

For example, in the case of IkBalpha,the inhibitor of the transcriptional regulator NF-kB, modification by SUMO-1 was shown to protect the substrate from ubiquitination

p(HGNC:NFKBIA, pmod(Sumo)) decreases bp(GO:"protein ubiquitination") View Subject | View Object

Appears in Networks:

p(HGNC:SUMO1) increases p(HGNC:NFKBIA, pmod(Sumo)) View Subject | View Object

Appears in Networks:

Evidence d7f480cebc
JSON

Interestingly, one of the DJ-1 mutations that is associated with AR-JP is a point mutation, L166P.

p(HGNC:PARK7, var("p.Leu166Pro")) association path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:

path(MESH:"Parkinsonian Disorders") association p(HGNC:PARK7, var("p.Leu166Pro")) View Subject | View Object

Appears in Networks:

Evidence c254421fe3
JSON

Various deletion and point mutations in the gene have been found in ~50% of patients with AR-JP (known also as Autosomal Recessive Parkinson’s Disease [ARPD]), one of the most common familial forms of PD (Kitada et al., 1998).

p(HGNC:PRKN, var("?")) increases path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:

Evidence c6a9020b22
JSON

An interesting finding is that not all mutations found in Parkin in AR-JP patients are inactivatingmutations (see,for example, Chung et al., 2001; Corti et al., 2003; Imai et al., 2001

p(HGNC:PRKN, var("?")) decreases act(p(HGNC:PRKN)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinsonian Disorders

Evidence 87118ed6c8
JSON

Therefore, patients with AR-JP—who cannot degrade it because of the mutation in the Parkin E3 (see above)—develop neurodegeneration

p(HGNC:PRKN, var("?")) causesNoChange deg(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinsonian Disorders

path(MESH:"Parkinsonian Disorders") increases path(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinsonian Disorders

Evidence eab40ec683
JSON

An interesting point is that the mutated Parkin species K161N, which is associated with AR-JP, could still ubiquitinate p38, suggesting that it is not loss of function that underlies the human disease (see above).

p(HGNC:PRKN, var("p.Lys161Asn")) association path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:

p(HGNC:PRKN, var("p.Lys161Asn")) increases p(HGNC:AIMP2, pmod(Ub)) View Subject | View Object

Appears in Networks:

path(MESH:"Parkinsonian Disorders") association p(HGNC:PRKN, var("p.Lys161Asn")) View Subject | View Object

Appears in Networks:

Evidence dcaaf96be6
JSON

Interestingly, dorfin expression is increased in the spinal cord of ALS patients (Ishigaki et al., 2002), which may suggest that the expression of the E3 ligase is increased in an attempt to enhance clearance of the mutant SOD1.

p(HGNC:RNF19A) increases deg(p(HGNC:SOD1, var("?"))) View Subject | View Object

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") increases p(HGNC:RNF19A) View Subject | View Object

Appears in Networks:

Evidence 1eae35b180
JSON

It is important to note that while mutations in the nonglycosylated 14 kDa form of alphaSYN have been linked to the pathogenesis of PD (see below), to date, they have not been linked with Parkin-associated AR-JP.

p(HGNC:SNCA, var("?")) association path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:

path(MESH:"Parkinsonian Disorders") association p(HGNC:SNCA, var("?")) View Subject | View Object

Appears in Networks:

Evidence a3a1ba4d98
JSON

In the late 1990s, it was reported that two mutations in the N-terminal domain of alphaSYN, A30P (Kruger et al., 1998) and A53T (Polymeropoulos et al., 1997), were associated with a rare form of autosomal-dominant familial PD

p(HGNC:SNCA, var("p.Ala30Pro")) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

p(HGNC:SNCA, var("p.Ala53Thr")) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Parkinson Disease") association p(HGNC:SNCA, var("p.Ala30Pro")) View Subject | View Object

Appears in Networks:

path(MESH:"Parkinson Disease") association p(HGNC:SNCA, var("p.Ala53Thr")) View Subject | View Object

Appears in Networks:

Evidence a5f8d65e34
JSON

The mutant proteins have a higher tendency to generate protofibrils

p(HGNC:SNCA, var("p.Ala30Pro")) increases a(HBP:"alpha-synuclein fibrils") View Subject | View Object

Appears in Networks:

p(HGNC:SNCA, var("p.Ala53Thr")) increases a(HBP:"alpha-synuclein fibrils") View Subject | View Object

Appears in Networks:

Evidence 86303bb26d
JSON

Alternatively, the enzyme itself may misfold and generate protein aggregates, thereby implicating a role for the UPS in disease pathogenesis (Cleveland and Liu, 2000; Julien, 2001;Valentine and Hart, 2003).

p(HGNC:SOD1, pmod(HBP:misfolding)) increases a(HBP:"protein aggregates") View Subject | View Object

Appears in Networks:

Evidence 49a13d828f
JSON

Further supporting this hypothesis is the finding of Cummings and collaborators (Cummings et al., 1999) that inactivation of the gene coding for the E6-AP (Ube3a) ligase in a transgenic model of SCA-1 resulted in a reduced number of neurons containing intranuclear aggregates (see below).

p(HGNC:UBE3A) increases complex(a(HBP:"protein aggregates"), a(MESH:Neurons)) View Subject | View Object

Appears in Networks:

Evidence fdce0b02e5
JSON

Interestingly, the expression of the inactive E3 increased the number of the dying Purkinje cells

act(p(HGNC:UBE3A)) decreases bp(GO:"cell death") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
Purkinje cell

Evidence 27a59b9f07
JSON

Spinal cords from sporadic ALS cases also express increased levels of the gene for ubiquitin-like protein 5.

p(HGNC:UBL5) positiveCorrelation path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord

path(MESH:"Amyotrophic Lateral Sclerosis") positiveCorrelation p(HGNC:UBL5) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord

Evidence 7319a24b22
JSON

Recent findings in a German family with PD have revealed a mutation in the gene coding for the ubiquitin carboxy-terminal hydrolase UCH-L1 (Leroy et al., 1998).

p(HGNC:UCHL1, var("?")) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Parkinson Disease") association p(HGNC:UCHL1, var("?")) View Subject | View Object

Appears in Networks:

Evidence 7dcbe928b2
JSON

The simple explanation is that the mutation leads to a shortage in free ubiquitin that should have been recycled from conjugates, which results in general impairment of the function of the UPS.

p(HGNC:UCHL1, var("?")) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 190fa67931
JSON

Themutation inUCH-L1 that was found linked to PD was identified as I93M

path(MESH:"Parkinson Disease") association p(HGNC:UCHL1, var("p.Ile93Met")) View Subject | View Object

Appears in Networks:

p(HGNC:UCHL1, var("p.Ile93Met")) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

Evidence f69872da77
JSON

On the other hand, RING finger-containing E3s catalyze, most probably, direct transfer of the activated ubiquitin moiety from E2 to the E3 bound substrate

p(INTERPRO:"E3 ubiquitin ligase RBR family") decreases complex(a(MESH:Ubiquitin), p(HGNC:UBA2)) View Subject | View Object

Appears in Networks:

p(INTERPRO:"E3 ubiquitin ligase RBR family") increases complex(a(MESH:Proteins), a(MESH:Ubiquitin), p(HGNC:UBA3)) View Subject | View Object

Appears in Networks:

Evidence 2bc0f153f3
JSON

Most of the point mutations described in Parkin reside in its RING-IBR-(In Between- RINGS)-RING domain and result in its inactivation (Lucking et al., 2000).

p(INTERPRO:"IBR domain", var("?")) decreases act(p(HGNC:PRKN)) View Subject | View Object

Appears in Networks:

Evidence 68c668fdef
JSON

Thus, Rad23 and Dsk2 in yeast are believed to bind polyubiquitinated substrates in the cytosol and target them to the proteasome

p(UNIPROT:P32628) increases tloc(p(MESH:Proteins, pmod(Ub)), fromLoc(GO:cytosol), toLoc(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

p(UNIPROT:P48510) increases tloc(p(MESH:Proteins, pmod(Ub)), fromLoc(GO:cytosol), toLoc(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence f84e9cbce8
JSON

In AD, the dominant symptom is dementia, initially characterized by a loss of short-term memory which gradually develops into a loss of most higher faculties

path(MESH:"Alzheimer Disease") increases path(MESH:Dementia) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases bp(GO:"short-term memory") View Subject | View Object

Appears in Networks:

Evidence 3728396b89
JSON

Patients with AD display two types of protein deposits: extracellular amyloid plaques and intracellular neurofibrillary tangles (Hardy and Selkoe, 2002).

path(MESH:"Alzheimer Disease") increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") increases a(MESH:"Neurofibrillary Tangles") View Subject | View Object

Appears in Networks:

Evidence 21b1288254
JSON

There are different forms of amyotrophic lateral sclerosis (ALS), all primarily display widespread death of brainstem and spinal motoneurons, corticospinal degeneration, paralysis of skeletal muscle, and eventual neuronal cell death

path(MESH:"Amyotrophic Lateral Sclerosis") decreases a(MESH:"Brain Stem") View Subject | View Object

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") decreases bp(GO:"spinal cord development") View Subject | View Object

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") decreases a(MESH:"Pyramidal Tracts") View Subject | View Object

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") increases path(MESH:Paralysis) View Subject | View Object

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:

Evidence 8b807f9594
JSON

They have in common a progressive development of severe motor disturbance and dementia leading to death within a fewmonths to a fewyears after diagnosis,which can be years to decades after the initial infection in transmissible cases.

path(MESH:"Prion Diseases") increases path(MESH:"Motor Disorders") View Subject | View Object

Appears in Networks:

path(MESH:"Prion Diseases") increases path(MESH:Dementia) View Subject | View Object

Appears in Networks:

path(MESH:"Prion Diseases") increases path(MESH:Death) View Subject | View Object

Appears in Networks:

Evidence b8e786b063
JSON

Prion disease neuropathology is characterized by widespread neuronal death, accompanied by spongiform vacuolation and astrogliosis, usually combined with widespread deposits of extracellular amyloid aggregates.

path(MESH:"Prion Diseases") increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:

path(MESH:"Prion Diseases") increases path(MESH:Gliosis) View Subject | View Object

Appears in Networks:

path(MESH:"Prion Diseases") increases a(HBP:"amyloid-beta aggregates") View Subject | View Object

Appears in Networks:

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.