PubMed: 14556719

The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg.
Brundin P | Ciechanover A

Evidence 7ee5b65614

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

Evidence dbfd08b0ae

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).

Evidence 34d70a233c

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).

Evidence ba28a25cfc

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)

Evidence 00a897038b

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.

Evidence 1095df09a9

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.

Evidence 2143cf0fde

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.

Evidence 4bef6b9daa

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).

Evidence 8af48b16b2

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.

Evidence 2312b4cbe2

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)

Evidence c4ee53d230

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

Evidence 4660bcddab

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

Evidence ca2c26afae

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

Evidence 1c14b09c64

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

Evidence 3ea6fc23ba

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

Evidence baffa24dac

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

Evidence ef9d279c7d

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).

Evidence fbbf758dd5

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

Evidence 2c721306ab

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

Evidence 3b2795549b

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

Evidence 6c0e5be3d6

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

Evidence d407963904

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

Evidence 56a320fd77

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

Evidence 25a0475584

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

Evidence 22afca4cdf

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

Evidence d0cad431f8

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

Evidence f249de0a16

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

Evidence a56eb5e830

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).

Evidence c52fbc2fc0

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

Evidence 0492162cd7

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

Evidence 270f55ed21

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).

Evidence af56e030ce

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

Evidence 6ec0d74b24

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

Evidence 3a845e7be8

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.

Evidence 8292d96517

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.

Evidence d8d0e86b44

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

Evidence 3258fd53d2

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

Evidence 33700ccf28

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.

Evidence 7272fb75c0

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

Evidence 60afb5ed62

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).

Evidence c6ac390296

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

Evidence 5f5c856ff4

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

Evidence 565f2c1861

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.

Evidence bef1f270dd

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.

Evidence eac614c5c6

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

Evidence 47b535fc71

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

Evidence 5314d44247

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

Evidence 09eeb79010

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

Evidence 0566c6a9b7

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

Evidence c3a3e99d72

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

Evidence f780fa3eea

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

Evidence feef7fd40f

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).

Evidence 23dec23851

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

Evidence 88b900d936

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

Evidence 0938de507b

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

Evidence dd58639d16

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

Evidence ee1383d275

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.

Evidence 9713594572

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.

Evidence 38a293d898

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).

Evidence df98747608

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

Evidence e6522ac74b

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

Evidence 65979e8f99

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

Evidence 74c542809a

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

Evidence 585e009b2f

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).

Evidence 5d6303efa9

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).

Evidence 662dc8809b

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

Evidence 752502934d

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).

Evidence c9fc3f70ad

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

Evidence 8dcc2000cb

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

Evidence d6d0335618

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).

Evidence e812aafcda

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

Evidence f30764c429

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

Evidence c6bd2fa2fd

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

Evidence 8fdf01bbd5

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

Evidence 379010e5f5

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

Evidence 31b6d20d03

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)

Evidence 790b0fb965

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

Evidence 536e435a3e

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).

Evidence 321d109e02

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

Evidence a8024297a4

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

Evidence e29a6ab50f

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

Evidence 195ba7f6bb

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

Evidence af1decb255

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

Evidence 168c955bf2

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).

Evidence 2621089c91

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.

Evidence 63f4bfb4cb

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

Evidence 9b000e558a

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

Evidence 73e72bccdc

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

Evidence b143923c9a

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

Evidence 23cf26fafa

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.

Evidence 6300a62586

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

Evidence 7062bd6ec1

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

Evidence 6d8b44ba93

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

Evidence 24cd81c3b5

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).

Evidence 5ec25cc1ce

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

Evidence 2f9f84080d

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).

Evidence bc8178185f

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

Evidence e0ea7f09b9

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

Evidence 08e7ade79d

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

Evidence 147943b3ef

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.

Evidence 35d434e27c

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).

Evidence 656f12255e

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

Evidence 90bf25d564

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

Evidence 540be357e3

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

Evidence 82d719e41a

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).

Evidence 86e60419f9

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

Evidence f8ce284b30

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

Evidence 54d105f14d

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).

Evidence 29eb009f7a

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).

Evidence a58fa8c137

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

Evidence c61c99cd67

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

Evidence 203c683ec1

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

Evidence 00b51b285b

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

Evidence 56be8aeea6

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

Evidence af3fffec3b

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).

Evidence 302596ea7f

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).

Evidence 3a98c4d7b1

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

Evidence a922b85444

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).

Evidence 10c5a8ada3

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

Evidence 826af9c02f

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

Evidence 54a1a554ea

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).

Evidence 08dfe3857b

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).

Evidence b8a9ea97eb

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)

Evidence 358eb7c400

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).

Evidence 6475640f8b

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

Evidence 165bf8958f

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

Evidence d7f480cebc

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

Evidence c254421fe3

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).

Evidence c6a9020b22

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

Evidence 87118ed6c8

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

Evidence eab40ec683

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).

Evidence dcaaf96be6

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.

Evidence 1eae35b180

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.

Evidence a3a1ba4d98

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

Evidence a5f8d65e34

The mutant proteins have a higher tendency to generate protofibrils

Evidence 86303bb26d

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).

Evidence 49a13d828f

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).

Evidence fdce0b02e5

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

Evidence 27a59b9f07

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

Evidence 7319a24b22

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).

Evidence 7dcbe928b2

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.

Evidence 190fa67931

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

Evidence f69872da77

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

Evidence 2bc0f153f3

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).

Evidence 68c668fdef

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

Evidence f84e9cbce8

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

Evidence 3728396b89

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

Evidence 21b1288254

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

Evidence 8b807f9594

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.

Evidence b8e786b063

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


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