1. Catalog
  2. Citations
  3. PubMed:30116051

PubMed: 30116051

Title
Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.
Journal
Nature reviews. Drug discovery
Volume
17
Issue
None
Pages
660-688
Date
2018-09-01
Authors
Boland B | Millan MJ | Bezard E | Corti O | Duchen MR | Eskelinen EL | Henriques A | Kroemer G | Levine B | Louis C | Mallucci GR | Martin OR | Mochel F | Mollereau B | Nixon RA | Pastores GM | Rubinsztein DC | Spedding M | Yu WH

Evidence 60b901cac6
JSON

Second, the TFEB inducer 2-hydroxypropyl-β-cyclo- dextrin promoted the acidity of lysosomes in neurons 190 .

a(PUBCHEM:129688311) increases bp(GO:"lysosomal lumen acidification") View Subject | View Object

Appears in Networks:

Evidence 6605c484c2
JSON

In regard to pharmacological manipulation, substances such as epigallocatechin and somatostatin promote the expression, secretion and (allosterically) catalytic activ- ity of IDE and neprilysin in parallel with an increase in the degradation of Aβ peptides 259,280 .

a(CHEBI:"(-)-epigallocatechin") increases p(HGNC:IDE) View Subject | View Object

Appears in Networks:

a(CHEBI:"(-)-epigallocatechin") increases sec(p(HGNC:IDE)) View Subject | View Object

Appears in Networks:

a(CHEBI:"(-)-epigallocatechin") increases act(p(HGNC:IDE)) View Subject | View Object

Appears in Networks:

a(CHEBI:"(-)-epigallocatechin") increases p(HGNC:MME) View Subject | View Object

Appears in Networks:

a(CHEBI:"(-)-epigallocatechin") increases sec(p(HGNC:MME)) View Subject | View Object

Appears in Networks:

a(CHEBI:"(-)-epigallocatechin") increases act(p(HGNC:MME)) View Subject | View Object

Appears in Networks:

a(CHEBI:somatostatin) increases p(HGNC:IDE) View Subject | View Object

Appears in Networks:

a(CHEBI:somatostatin) increases sec(p(HGNC:IDE)) View Subject | View Object

Appears in Networks:

a(CHEBI:somatostatin) increases act(p(HGNC:IDE)) View Subject | View Object

Appears in Networks:

a(CHEBI:somatostatin) increases p(HGNC:MME) View Subject | View Object

Appears in Networks:

a(CHEBI:somatostatin) increases sec(p(HGNC:MME)) View Subject | View Object

Appears in Networks:

a(CHEBI:somatostatin) increases act(p(HGNC:MME)) View Subject | View Object

Appears in Networks:

Evidence 80c7e100a6
JSON

Indeed, clioquinol countered disruption of autophagy by chloroquine in retinal cells, reduced Aβ42 accumulation in CHO cells expressing APP and mutant presenilin 1 and diminished amyloid misfolding and aggregation in Tg2576 AD mice 196,197 .

a(CHEBI:"5-chloro-7-iodoquinolin-8-ol") increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

a(CHEBI:"5-chloro-7-iodoquinolin-8-ol") decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:

a(CHEBI:chlorohydroquinone) decreases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence 2bfa02b5e2
JSON

The aminoimidazole derivative 5-aminoimidazole- 4-carboxamide ribonucleotide (AICAR) undergoes intra- cellular transformation to an AMP analogue that triggers AMPK-mediated autophagy 21,108 .

a(CHEBI:"AICA ribonucleotide") increases act(p(FPLX:AMPK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

act(p(FPLX:AMPK)) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence c3efd3831c
JSON

In addition, calcitriol (the active metabolite of vitamin D 3 ) elicited AMPK-dependent autophagy in a neurochemical lesion-induced model of PD 129.

a(CHEBI:calcitriol) increases act(p(FPLX:AMPK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

a(CHEBI:calcitriol) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

Evidence 7eaa91ff19
JSON

Because the class III deacetylase NAD- dependent protein deacetylase sirtuin 1 (SIRT1) requires nicotinamide adenine dinucleotide (NAD) to sustain its activity, this positive regulator of autophagy may also be considered a sensor 24 .

a(CHEBI:"NAD(+)") increases act(p(HGNC:SIRT1)) View Subject | View Object

Appears in Networks:

p(HGNC:SIRT1) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence dd66d657a8
JSON

SIRT1 is activated by AMPK- mediated increases in nicotinamide, and it drives the ALN by inhibiting mTORC1, inducing FOXO1 and FOXO3 and activating key regulatory proteins such as ATG5, ATG7 and LC3.

a(CHEBI:"NAD(+)") increases act(p(HGNC:SIRT1)) View Subject | View Object

Appears in Networks:

p(FPLX:AMPK) increases a(CHEBI:"NAD(+)") View Subject | View Object

Appears in Networks:

act(p(HGNC:SIRT1)) decreases act(p(FPLX:mTORC1)) View Subject | View Object

Appears in Networks:

act(p(HGNC:SIRT1)) increases act(p(HGNC:FOXO1)) View Subject | View Object

Appears in Networks:

act(p(HGNC:SIRT1)) increases act(p(HGNC:FOXO3)) View Subject | View Object

Appears in Networks:

act(p(HGNC:SIRT1)) increases act(p(HGNC:ATG5)) View Subject | View Object

Appears in Networks:

act(p(HGNC:SIRT1)) increases act(p(HGNC:ATG7)) View Subject | View Object

Appears in Networks:

act(p(HGNC:SIRT1)) increases act(p(HGNC:MAP1LC3A)) View Subject | View Object

Appears in Networks:

Evidence 3018298de2
JSON

The di-glucose derivative trehalose inhibits the sol- ute carrier 2A (SLC2A) family of glucose transporters to promote AMPK-induced autophagy and reduce neurotoxic protein load, although it also exerts other actions downstream in the ALN 4,120 .

a(CHEBI:"alpha,alpha-trehalose") decreases act(p(HGNC:SLC2A9)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"alpha,alpha-trehalose") increases act(p(FPLX:AMPK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

act(p(FPLX:AMPK)) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence de07729779
JSON

It also proved effective in cellu- lar models of PD, HD and AD 121,122 , as well as in mouse models of HD, AD and tauopathies, where it cleared aggregates, reduced neurodegeneration and ameliorated motor and cognitive performance 123–125 .

a(CHEBI:"alpha,alpha-trehalose") decreases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"alpha,alpha-trehalose") decreases a(HBP:HBP00006) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"alpha,alpha-trehalose") decreases a(HBP:HBP00016) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"alpha,alpha-trehalose") decreases a(HBP:HBP00017) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"alpha,alpha-trehalose") decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"alpha,alpha-trehalose") increases bp(GO:"motor behavior") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"alpha,alpha-trehalose") increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 964d1ef97d
JSON

Sixth, Aβ42 compro- mises the function of AMPK to impede initiation of the ALN 67 .

a(CHEBI:"amyloid-beta polypeptide 42") decreases act(p(FPLX:AMPK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta polypeptide 42") decreases bp(GO:"autophagosome assembly") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 0ff21f916e
JSON

Seventh, Aβ42 obstructs the UPS and CMA 47,68 .

a(CHEBI:"amyloid-beta polypeptide 42") decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta polypeptide 42") decreases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 8beed3c8f9
JSON

The UPS and CMA are disrupted by neurotoxic proteins like Aβ42 and tau, hence, their early and preventive reinforcement prior to Aβ42 and tau accumulation may be critical.

a(CHEBI:"amyloid-beta polypeptide 42") decreases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Appears in Networks:

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

Appears in Networks:

Evidence 8945c6d390
JSON

The microtubule stabilizers paclitaxel and epothilone A countered Aβ42-induced cytoskeletal disruption — and moderated excessive UPR — in neurons 182 .

a(CHEBI:"epothilone A") increases a(GO:microtubule) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:"amyloid-beta polypeptide 42") decreases a(GO:microtubule) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:paclitaxel) increases a(GO:microtubule) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

Evidence 1770905df0
JSON

In a vicious circle, Aβ42 itself decreases IDE expression, although it may prompt its release from glia 254,259 .

a(CHEBI:"amyloid-beta polypeptide 42") decreases p(HGNC:IDE) View Subject | View Object

Appears in Networks:

Evidence 965e2193b1
JSON

Furthermore, epothilone D countered microtubule disruption and cognitive deficits in aged P301S/P19 AD mice 183 .

a(CHEBI:"epothilone D") increases a(GO:microtubule) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:"epothilone D") increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

Evidence b843c4e076
JSON

Lithium ions inhibit inositol monophosphatase to deplete inositol triphosphate.

a(CHEBI:"lithium(1+)") decreases act(p(HGNC:IMPA1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"lithium(1+)") decreases a(PUBCHEM:55310) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 25f0fad81d
JSON

This mechanism may be involved in its promotion of autophagy, reduction in cel- lular levels of α-synuclein, SOD1, Htt and tau 126 , ame- lioration of motor function in a P301L mouse model of tauopathy 127 and slowing of disease progression in SOD1 mice 128 .

a(CHEBI:"lithium(1+)") increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"lithium(1+)") decreases p(HGNC:SNCA) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"lithium(1+)") decreases p(HGNC:SOD1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"lithium(1+)") decreases p(HGNC:HTT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"lithium(1+)") decreases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"lithium(1+)") increases bp(GO:"motor behavior") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 117b783b3a
JSON

For example, methylene blue coun- ters tau oligomerization and promotes autophagy 101,102 (Supplementary Table 4).

a(CHEBI:"methylene blue") decreases a(HBP:HBP00009) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"methylene blue") increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 68b7193096
JSON

Other compounds that act through AMPK acti- vation include the antiaggregant methylene blue (Supplementary Box 1), which elevated levels of beclin  1, p62 and LC3, induced autophagy and suppressed tau in organotypic neuronal cultures and a mouse model of FTD 101,102 .

a(CHEBI:"methylene blue") increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"methylene blue") increases act(p(FPLX:AMPK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"methylene blue") increases p(HGNC:BECN1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"methylene blue") increases p(HGNC:MAP1LC3A) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"methylene blue") increases p(HGNC:DCTN4) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"methylene blue") decreases act(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 7e69838899
JSON

Third, acidic nanoparticles such as polylactic acid and poly(lactide- co-glycolide) increase acidification (BOX 3) .

a(CHEBI:"poly(D,L-lactic acid-co-glycolic acid)") increases bp(GO:"lysosomal lumen acidification") View Subject | View Object

Appears in Networks:

a(CHEBI:"poly(lactic acid) polymer") increases bp(GO:"lysosomal lumen acidification") View Subject | View Object

Appears in Networks:

Evidence 92392f3575
JSON

Selenium deficits have been linked to AD, and thus it is interesting that seleno- methionine boosted ALN flux, from AMPK recruit- ment through autophagosome formation to lysosomal degradation, in the 3×Tg AD mouse model 112 .

a(CHEBI:"selenium(2+)") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:selenomethionine) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:selenomethionine) increases act(p(FPLX:AMPK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:selenomethionine) increases bp(GO:"autophagosome assembly") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:selenomethionine) increases bp(GO:"lysosomal microautophagy") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

path(MESH:"Alzheimer Disease") negativeCorrelation a(CHEBI:"selenium(2+)") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 337cce02cb
JSON

Calpeptin, a cell-permeable calpain inhibitor, can also reduce Htt proteinopathy via induction of autophagy 103,105 .

a(CHEBI:Calpeptin) decreases act(p(HGNC:CAPN1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

a(CHEBI:Calpeptin) decreases act(p(HGNC:CAPN2)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

a(CHEBI:Calpeptin) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

a(CHEBI:Calpeptin) increases deg(p(HGNC:HTT, var("?"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

Evidence 37932477d3
JSON

In addition, the plant-derived alkaloid isorhynchophylline upregulated beclin 1 independently of mTORC1 and promoted autophagic clearance of α-synuclein, although its precise mechanism of action remains to be clarified 175 .

a(CHEBI:Isorhynchophylline) increases p(HGNC:BECN1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:Isorhynchophylline) decreases a(HBP:HBP00016) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

Evidence 4c808a1dc8
JSON

Indeed, clonidine and rilmenidine, two G i /G o -coupled α 2 -adrenergic receptor and imidazoline 1 receptor agonists, stimulate autophagy and cleared Htt in cellular 103 and animal models of HD 104 .

a(CHEBI:Rilmenidine) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

a(CHEBI:Rilmenidine) increases deg(p(HGNC:HTT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

a(CHEBI:clonidine) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

a(CHEBI:clonidine) increases deg(p(HGNC:HTT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

Evidence ae192b19c7
JSON

Likewise, temsirolimus reduced the accumulation of phosphorylated tau in SH-SY5Y cells and P301S tauopathy mice 137 .

a(CHEBI:Temsirolimus) decreases a(HBP:HBP00006) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 2875168f88
JSON

It also removed cellular aggregates of mutant Htt and improved motor performance in a mouse model of HD, reduced α-synuclein aggregation and afforded neuroprotection in a lesion-based model of PD and depleted mutant ataxin 3 in a mouse model of supraspinal cerebellar ataxia type 3 (REFS133,138,139) .

a(CHEBI:Temsirolimus) decreases a(HBP:HBP00017) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

a(CHEBI:Temsirolimus) increases bp(GO:"motor behavior") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

a(CHEBI:Temsirolimus) decreases a(HBP:HBP00016) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

a(CHEBI:Temsirolimus) decreases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

a(CHEBI:Temsirolimus) decreases p(HGNC:ATXN3, var("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

Evidence 04949e8fc1
JSON

It increased expression of βGCase, normalized autophagy and accelerated degradation of α-synuclein in a stem cell model of dopaminergic neurons derived from patients with PD bearing mutations in βGCase 200 .

a(CHEBI:ambroxol) increases p(HGNC:GBA) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

a(CHEBI:ambroxol) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

a(CHEBI:ambroxol) increases deg(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

Evidence 8e82c62887
JSON

Ambroxol, which also decreased ER stress in D. mela- nogaster 201 , reduced α-synuclein levels in overexpress- ing, transgenic mice 202 .

a(CHEBI:ambroxol) decreases p(HGNC:SNCA) View Subject | View Object

Appears in Networks:

a(CHEBI:ambroxol) decreases bp(GO:"response to endoplasmic reticulum stress") View Subject | View Object

Appears in Networks:

Evidence 2384e25456
JSON

Cilostazol (a phosphodiesterase 3 inhibitor) clears Aβ42 from neuronal cell lines by promoting autophagy, upregulating beclin 1, ATG5 and LC3, downregulating mTORC1 and inducing lysosomal cathepsin B; these actions of cilostazol involve activation of SIRT1 as well as upstream Tyr172 phosphorylation of AMPK 108,162,163 .

a(CHEBI:cilostazol) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:cilostazol) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:cilostazol) increases p(HGNC:BECN1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:cilostazol) increases p(HGNC:ATG5) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:cilostazol) increases p(HGNC:MAP1LC3A) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:cilostazol) decreases p(FPLX:mTORC1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:cilostazol) increases p(HGNC:CTSB) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Lysosomes
MeSH
Machado-Joseph Disease

a(CHEBI:cilostazol) increases act(p(HGNC:SIRT1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:cilostazol) increases p(FPLX:AMPK, pmod(Ph, Tyr, 172)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

Evidence 25ea3229ed
JSON

Cilostazol improved cognition and reduced levels of Aβ42 and hyperphosphorylated tau following intra- cerebroventricular injection of Aβ25–35 into mice 162,163 .

a(CHEBI:cilostazol) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:cilostazol) increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:cilostazol) decreases p(HGNC:MAPT, pmod(HBP:HBP00007)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

Evidence f517b9078c
JSON

The natural product curcumin induced macro- autophagy and protected rotenone-treated dopaminer- gic neurons 141 in addition to accelerating the elimination of mutant α-synuclein-A53T by repressing mTORC1 in a cellular model of early-onset PD, although it also exerts other actions such as inhibition of p300-mediated pro- tein acetylation and of aggregation 142,143 .

a(CHEBI:curcumin) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:curcumin) decreases act(p(FPLX:mTORC1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:curcumin) increases deg(p(HGNC:SNCA, var("p.Ala53Thr"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

Evidence 5b2236f8dc
JSON

Pro-autophagic effects of curcumin are reflected in improved function in cellular and animal models of PD and AD, as well as reduced levels of α-synuclein aggregates 144 or Aβ and tau oligomers 145,146 .

a(CHEBI:curcumin) decreases a(HBP:HBP00016) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:curcumin) decreases a(HBP:HBP00022) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:curcumin) decreases a(HBP:HBP00009) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

Evidence be0af7325d
JSON

Moreover, the flavonol fisetin stimulated auto- phagic degradation of phosphorylated tau in cortical neu- rons via mTORC1-dependent activation of TFEB and the cytoprotective transcription factor nuclear factor eryth- roid 2-related factor 2 (NFE2L2) 149 . Fisetin also reduced Aβ accumulation in an APP/PS1 mouse model of AD 150 .

a(CHEBI:fisetin) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:fisetin) increases act(p(FPLX:mTORC1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:fisetin) decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

bp(GO:macroautophagy) increases deg(p(HGNC:MAPT, pmod(HBP:HBP00007))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

act(p(FPLX:mTORC1)) increases act(p(HGNC:TFEB)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

act(p(FPLX:mTORC1)) increases act(p(HGNC:NFE2L2)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

Evidence f13048d024
JSON

Among compounds that inhibit HSP90, geldanamycin promoted elimination of both hyper- phosphorylated tau and oligomeric α-synuclein in cell lines 219,220 .

a(CHEBI:geldanamycin) decreases act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

a(CHEBI:geldanamycin) decreases p(HGNC:MAPT, pmod(HBP:HBP00007)) View Subject | View Object

Appears in Networks:

a(CHEBI:geldanamycin) decreases a(HBP:HBP00016) View Subject | View Object

Appears in Networks:

Evidence f278d8f987
JSON

The antidiabetic drug metformin, a prototypical activator of AMPK, induced autophagy and increased longevity in mice 116 .

a(CHEBI:metformin) increases act(p(FPLX:AMPK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:metformin) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence be09b6ad5b
JSON

Moreover, reductions in levels of hyper phosphorylated tau and Aβ were seen in metformin- treated neurons 117,118 , while it blunted neuronal loss in a neurochemical lesion model of PD in mice 119 .

a(CHEBI:metformin) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:metformin) decreases p(HGNC:MAPT, pmod(HBP:HBP00007)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:metformin) decreases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

Evidence 7e259dd7fe
JSON

Inactivation of ABL1 with brain-penetrant nilotinib conferred neuroprotective autophagy in mouse models of PD 153 .

a(CHEBI:nilotinib) decreases act(p(HGNC:ABL1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:nilotinib) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:nilotinib) decreases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

Evidence db0989afb6
JSON

The ‘anti-ageing’ agent resveratrol is thought to indi- rectly recruit AMPK via activation of calcium/calmodulin- dependent protein kinase kinase 2 (CAMKK2), which, acting in synergy with Ca 2+ , exerts its effects via Thr172 phosphorylation 113 . This action, among others (below), is involved in its reduction of Aβ levels in N2a cells and neurons 114 and the elimination of Aβ and Htt in animal models of AD and HD 114,115 .

a(CHEBI:resveratrol) increases act(p(HGNC:CAMKK2)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:resveratrol) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:resveratrol) decreases p(HGNC:HTT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

composite(a(CHEBI:"calcium(2+)"), p(HGNC:CAMKK2)) increases p(FPLX:AMPK, pmod(Ph, Thr, 172)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 55f87335b6
JSON

Resveratrol can stimulate SIRT1 via AMPK (see above), and it also possesses an AMPK-independent mode of SIRT1 recruitment that participates in blunting the neurotoxicity of Aβ25–35 fragments in PC12 cells 160 .

a(CHEBI:resveratrol) increases act(p(FPLX:AMPK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:resveratrol) decreases act(p(HGNC:APP, frag("23_35"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

act(p(FPLX:AMPK)) increases act(p(HGNC:SIRT1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

Evidence d14a83b1b0
JSON

The multi-modal agent resveratrol induced the expression of ATG4 and promoted autophagosome formation.

a(CHEBI:resveratrol) increases r(FPLX:ATG4) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:resveratrol) increases bp(GO:"autophagosome assembly") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

Evidence a90083f7eb
JSON

Interestingly, resver- atrol downregulated RAGE as well as MMP9 — an effect that is related to decreased hippocampal load of Aβ42 (REF.297) .

a(CHEBI:resveratrol) decreases p(HGNC:AGER) View Subject | View Object

Appears in Networks:

a(CHEBI:resveratrol) decreases p(HGNC:MMP9) View Subject | View Object

Appears in Networks:

a(CHEBI:resveratrol) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 11528ab402
JSON

The antibiotic rifampicin likewise promoted Aβ42 clearance by induc- ing BBB-localized LRP1 and P glycoprotein 1 (REFS273,292) .

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

Appears in Networks:

a(CHEBI:rifampicin) increases act(p(HGNC:LRP1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Blood-Brain Barrier

a(CHEBI:rifampicin) increases act(p(FPLX:"GPIb_IX_V")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Blood-Brain Barrier

Evidence d17c8e5d29
JSON

Enhancing auto- phagy with rapamycin reduced levels of α-synuclein, FUS and Htt 130–132 .

a(CHEBI:sirolimus) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:sirolimus) decreases p(HGNC:SNCA) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:sirolimus) decreases p(HGNC:FUS) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:sirolimus) decreases p(HGNC:HTT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 4700b0a723
JSON

Spermidine inhibits the acetylation of ATG7 and histone H3, while induc- ing beclin 1 via blockade of its cleavage by caspase 3 (REF.168) .

a(CHEBI:spermidine) decreases p(HGNC:ATG7, pmod(Ac)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:spermidine) decreases p(FPLX:"Histone_H3", pmod(Ac)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:spermidine) increases act(p(HGNC:BECN1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(CHEBI:spermidine) decreases act(p(HGNC:CASP3)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

p(HGNC:BECN1, frag("?")) decreases act(p(HGNC:BECN1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

act(p(HGNC:CASP3)) increases p(HGNC:BECN1, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

Evidence f27d7fc24a
JSON

The less cytotoxic analogue of geldanamycin, 17-AAG, has improved brain penetrance. It decreased Aβ levels 223 , improved memory 224 and lowered tau in transgenic AD mice 224 . 17-AAG also reduced α-synuclein oligomers in H4 cells 220 .

a(CHEBI:tanespimycin) decreases act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

a(CHEBI:tanespimycin) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:tanespimycin) increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:tanespimycin) decreases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:tanespimycin) decreases a(HBP:HBP00016) View Subject | View Object

Appears in Networks:

Evidence f6ef14af5d
JSON

Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 .

a(HBP:HBP00006) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

complex(GO:"proteasome complex") increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(HBP:HBP00007)) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 35b8b0ec32
JSON

Finally, while physiological tau possesses KFERQ motifs and is degraded by CMA, aggregates, mutant forms and frag- ments interfere with CMA 45,47 .

a(HBP:HBP00006) decreases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, frag("?")) decreases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, var("?")) decreases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence a5d88a4394
JSON

Sixth, aggregates and mutant forms of α-synuclein disrupt the proteasome in dopaminergic neurons.

a(HBP:HBP00016) decreases complex(GO:"proteasome complex") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

Evidence 70c22f9e66
JSON

Third, apolipoprotein E allele 4 (APOE4), a major risk allele for sporadic AD, is associated with increased generation and accumula- tion of Aβ42 (REFS59,60) .

a(HBP:HBP00030) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:HBP00030) increases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 3376eece4f
JSON

In addition to decreased degradation, one consequence is leakage of asparaginyl endopeptidase into the cytosol, where it generates toxic fragments of tau 61 .

a(HBP:HBP00030) increases p(HGNC:LGMN) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cytosol
MeSH
Alzheimer Disease

p(HGNC:LGMN) increases p(HGNC:MAPT, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cytosol
MeSH
Alzheimer Disease

Evidence 2b4921b600
JSON

Harnessing TFEB by 2-hydroxypropyl-β-cyclodextrin promoted clearance of proteolipid aggregates and α-syn- uclein in a cellular model of PD 195,204 .It also augmented the elimination of Aβ in a Tg19959/CRND8 mouse model of AD 173 .

a(PUBCHEM:129688311) decreases a(HBP:HBP00016) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

a(PUBCHEM:129688311) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 3f90c121de
JSON

An unusual approach to augmenting autophagosome formation is represented by the brain- penetrant autophagy enhancer 99 (AUTEN-99), which blocks myotubularin-related protein 14 (MTMR14, also known as Jumpy), a phosphatase that inhibits the phos- phoinositide 3-kinase (PI3K)-mediated generation of the autophagosome membrane (FIG. 3) . AUTEN-99 aug- mented autophagic flux in isolated neurons, increased markers of autophagy in mouse brain and slowed neuro- degeneration in D. melanogaster models of PD and HD 181 .

a(PUBCHEM:16240819) decreases act(p(HGNC:MTMR14)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(PUBCHEM:16240819) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

a(PUBCHEM:16240819) decreases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

act(p(FPLX:PI3K)) increases a(GO:"autophagosome membrane") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

p(HGNC:MTMR14) decreases act(p(FPLX:PI3K)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

Evidence d68097faf9
JSON

Fourth, activation of the lysosomal Ca 2+ channel mucol- ipin transient receptor potential channel 1 (TRPML1) with a synthetic agonist (ML-SA1) increased lysoso- mal Ca 2+ release, lowered pH and promoted Aβ clear- ance 191,192 .

a(PUBCHEM:2880983) increases act(p(HGNC:MCOLN1)) View Subject | View Object

Appears in Networks:

act(p(HGNC:MCOLN1)) increases tloc(a(CHEBI:"calcium(2+)"), fromLoc(MESH:Lysosomes), toLoc(MESH:Cytoplasm)) View Subject | View Object

Appears in Networks:

act(p(HGNC:MCOLN1)) increases bp(GO:"lysosomal lumen acidification") View Subject | View Object

Appears in Networks:

act(p(HGNC:MCOLN1)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

Evidence ffd21e45f1
JSON

Chronic administration of CGS-21680, a selective agonist of the AC-coupled adenosine A 2A receptor, restored proteasomal activity in cellular and murine models for HD via PKA-mediated Ser120 phosphorylation of the RPT6 component of the 19S subunit 231 .

a(PUBCHEM:3086599) increases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

a(PUBCHEM:3086599) increases act(p(FPLX:PKA), ma(kin)) View Subject | View Object

Appears in Networks:

act(p(FPLX:PKA), ma(kin)) increases p(HGNC:PSMC5, pmod(Ph, Ser, 120)) View Subject | View Object

Appears in Networks:

Evidence 7cb828fa9b
JSON

Another HSP90 inhibitor, HSP990, has shown promise in lowering Htt aggregates and improving motor performance in two mouse models of HD 225 .

a(PUBCHEM:46216556) decreases act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

a(PUBCHEM:46216556) decreases a(HBP:HBP00017) View Subject | View Object

Appears in Networks:

Evidence e2ba775a53
JSON

Another direct facilitator of AMPK, A769662, elicited autophagy and reduced the burden of Htt in a striatal cell line derived from knock-in mice expressing a humanized form of mutant Htt (exon 1 containing seven polyglutamine repeats) 111 .

a(PUBCHEM:54708532) increases act(p(FPLX:AMPK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(PUBCHEM:54708532) increases deg(p(HGNC:HTT, var("?"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence fa776aff5a
JSON

One promising agent is the hydroxylamine deriva- tive arimoclomol, which increases the activity of HSP70 by augmenting transcriptional activity of HSF1 (REF.210) .

a(PUBCHEM:9568077) increases act(p(HGNC:HSF1), ma(tscript)) View Subject | View Object

Appears in Networks:

act(p(HGNC:HSF1), ma(tscript)) increases act(p(FPLX:HSPA)) View Subject | View Object

Appears in Networks:

Evidence 79e2990071
JSON

Tau, α-synuclein and TDP43 are substrates for CMA degradation, as are amyloid precursor protein (APP) but not amyloid-β fragment 42 (Aβ42) itself 3,45–47,48 .

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:TARDBP)) View Subject | View Object

Appears in Networks:

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:APP)) View Subject | View Object

Appears in Networks:

bp(GO:"chaperone-mediated autophagy") causesNoChange deg(a(CHEBI:"amyloid-beta polypeptide 42")) View Subject | View Object

Appears in Networks:

Evidence 8a13b5e343
JSON

CMA dysfunction in PD favours the accumulation of α- synuclein and leads to inactivation of the dopaminergic neuron survival factor, myocyte-specific enhancer factor 2D (MEF2D) 2,45,47,55 .

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

bp(GO:"chaperone-mediated autophagy") increases act(p(HGNC:MEF2D)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

Evidence b648e7840b
JSON

Htt is not efficiently cleared by CMA, and the same appears to hold for its fragments and mutant and post- translationally modified forms, although the precise role of CMA in Htt elimination remains to be more fully defined 2,45–47 .

bp(GO:"chaperone-mediated autophagy") causesNoChange deg(p(HGNC:HTT)) View Subject | View Object

Appears in Networks:

Evidence 4b86bad9a5
JSON

Interestingly, the UPS is important for elimination of tau and other neurotoxic proteins in post synaptic dendritic compartments (a key site of spreading), where it plays a more general role favouring synaptic plasticity, den- dritogenesis and memory formation 49,52 .

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

Appears in Networks:
Annotations
MeSH
Dendrites

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

Appears in Networks:
Annotations
MeSH
Dendrites

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

Appears in Networks:
Annotations
MeSH
Dendrites

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

Appears in Networks:
Annotations
MeSH
Dendrites

Evidence 27288b8b17
JSON

Activity of the deacetylase SIRT1 declines with age, partially owing to limited availability of its co fac- tor, nicotinamide 24,56,156 .

bp(GO:aging) decreases act(p(HGNC:SIRT1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

bp(GO:aging) decreases a(CHEBI:"NAD(+)") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

Evidence cd75217283
JSON

Fourth, genetic mutations and anomalies of presenilin 1, a dominant negative gene linked to AD, are associated with reduced lysosomal v-ATPase-mediated acidifica- tion 40,63 , a compromised ALN and deficient mitophagy 64 .

bp(GO:autophagy) negativeCorrelation g(HGNC:PSEN1, var("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:mitophagy) negativeCorrelation g(HGNC:PSEN1, var("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

act(complex(GO:"lysosomal proton-transporting V-type ATPase complex")) negativeCorrelation g(HGNC:PSEN1, var("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

g(HGNC:PSEN1, var("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

g(HGNC:PSEN1, var("?")) negativeCorrelation act(complex(GO:"lysosomal proton-transporting V-type ATPase complex")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

g(HGNC:PSEN1, var("?")) negativeCorrelation bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

g(HGNC:PSEN1, var("?")) negativeCorrelation bp(GO:mitophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation g(HGNC:PSEN1, var("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 9e2bf480fc
JSON

Mutant Htt is cleared by autophagy, but it compromises the ALN because of decreased cargo load- ing and impaired autophagosome formation and trans- port 55,56,68,92 .

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

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:HTT, var("?")) decreases bp(GO:"cargo loading into vesicle") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:HTT, var("?")) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:HTT, var("?")) decreases bp(GO:"autophagosome assembly") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

Evidence 6d42282938
JSON

Some of these lead to an impairment of the ALN owing to reduced activation of beclin 1; another repercussion may be altered process- ing of APP, providing an unexpected link to AD 69,71–73 .

bp(HBP:HBP00073) association p(HGNC:LRRK2, var("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

p(HGNC:LRRK2, var("?")) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

p(HGNC:LRRK2, var("?")) decreases act(p(HGNC:BECN1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

p(HGNC:LRRK2, var("?")) association bp(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

Evidence 5735147d3b
JSON

This kinase is classically inactivated by rapamycin, which binds to the modulatory protein 12 kDa FK506-binding protein (FKBP12; also known as FKBP1A).

complex(a(CHEBI:sirolimus), p(HGNC:FKBP1A)) decreases act(p(FPLX:mTORC1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 73b9a8c1ea
JSON

Disruption of this Bcl-2–beclin 1 complex is an alternative approach for promoting autophagy, as achieved in mouse fibroblasts by the BH3 mimetic ABT-737 (REF.177) .

complex(p(HGNC:BCL2), p(HGNC:BECN1)) decreases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

Evidence ecd3667992
JSON

Activation of ULK1 triggers autophagosome nucleation through activating phospho- rylation of AMBRA and beclin 1 within the autophagy- specific PIK3C3 complex 10 (FIG. 3) .

act(p(HGNC:BECN1)) increases bp(GO:"autophagosome assembly") View Subject | View Object

Appears in Networks:

act(p(HGNC:AMBRA1)) increases bp(GO:"autophagosome assembly") View Subject | View Object

Appears in Networks:

p(HGNC:AMBRA1, pmod(Ph)) increases act(p(HGNC:AMBRA1)) View Subject | View Object

Appears in Networks:

p(HGNC:BECN1, pmod(Ph)) increases act(p(HGNC:BECN1)) View Subject | View Object

Appears in Networks:

act(p(HGNC:ULK1)) increases bp(GO:"autophagosome assembly") View Subject | View Object

Appears in Networks:

act(p(HGNC:ULK1)) increases p(HGNC:AMBRA1, pmod(Ph)) View Subject | View Object

Appears in Networks:

act(p(HGNC:ULK1)) increases p(HGNC:BECN1, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence 224737d83a
JSON

Third, cellular inhibitor of apoptosis 1 (CIAP1; also known as BIRC2) specifically binds mutant SOD1 and drives it to proteasomal degradation.

complex(p(HGNC:BIRC2), p(HGNC:SOD1)) increases deg(p(HGNC:SOD1)) View Subject | View Object

Appears in Networks:

Evidence 401f44fada
JSON

Another kinase that activates the proteasome (RPT6 subunit) — and directs it to dendritic spines — is CAMKK2 (REF.227) .

p(HGNC:CAMKK2) increases act(p(HGNC:PSMC5)) View Subject | View Object

Appears in Networks:

Evidence 665186c04b
JSON

Fifth, mutations in APP similarly disrupt endosomal and lysosomal func- tion, in part owing to accumulation of the β-secretase- generated, carboxy-terminal and Aβ42-containing fragment of APP called C99 (REF.66) .

g(HGNC:APP, var("?")) decreases act(a(GO:endosome)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

g(HGNC:APP, var("?")) decreases act(a(GO:lysosome)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

g(HGNC:APP, var("?")) increases a(HBP:HBP00081) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 8aea6da98d
JSON

The heterotrimeric serine/threonine kinase 5ʹ‑AMP‑ activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) trigger autophagy and repress mitophagy 3,10,20–23 (BOX 2; FIG. 3) .

p(FPLX:AMPK) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

p(FPLX:AMPK) decreases bp(GO:mitophagy) View Subject | View Object

Appears in Networks:

p(FPLX:mTORC1) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

p(FPLX:mTORC1) decreases bp(GO:mitophagy) View Subject | View Object

Appears in Networks:

Evidence fae977b7f9
JSON

AMPK is central to several mechanisms that trigger autophagy — most importantly, activating phosphoryla- tion of ULK1 (Ser317 and Ser777) and inhibitory phos- phorylation of mTORC1 (REFS21,31) .

p(FPLX:AMPK) increases p(HGNC:ULK1, pmod(Ph, Ser, 317)) View Subject | View Object

Appears in Networks:

p(FPLX:AMPK) increases p(HGNC:ULK1, pmod(Ph, Ser, 777)) View Subject | View Object

Appears in Networks:

p(FPLX:AMPK) increases p(FPLX:mTORC1, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(FPLX:mTORC1, pmod(Ph)) decreases act(p(FPLX:mTORC1)) View Subject | View Object

Appears in Networks:

p(HGNC:ULK1, pmod(Ph, Ser, 317)) increases act(p(HGNC:ULK1)) View Subject | View Object

Appears in Networks:

p(HGNC:ULK1, pmod(Ph, Ser, 777)) increases act(p(HGNC:ULK1)) View Subject | View Object

Appears in Networks:

Evidence 8d493a81d8
JSON

One major strategy for promoting autophagy is the relief of its repression by mTORC1.

p(FPLX:mTORC1) decreases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 92fa3cf46b
JSON

Conversely, mTORC1 inhibits ULK1 by Ser757 phosphorylation 3,4,31 .

p(FPLX:mTORC1) increases p(HGNC:ULK1, pmod(Ph, Ser, 757)) View Subject | View Object

Appears in Networks:

p(HGNC:ULK1, pmod(Ph, Ser, 757)) decreases act(p(HGNC:ULK1)) View Subject | View Object

Appears in Networks:

Evidence 51dd7b8c02
JSON

mTORC1 also restrains autophagy by preventing nuclear translo- cation of TFEB 20 .

p(FPLX:mTORC1) decreases tloc(p(HGNC:TFEB), fromLoc(MESH:Cytoplasm), toLoc(MESH:"Cell Nucleus")) View Subject | View Object

Appears in Networks:

tloc(p(HGNC:TFEB), fromLoc(MESH:Cytoplasm), toLoc(MESH:"Cell Nucleus")) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence 550585f147
JSON

Finally, mirroring its inhibitory influence on the ALN, mTORC1 suppresses the UPS by impeding the formation and assembly of proteasomal subunits.

p(FPLX:mTORC1) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

p(FPLX:mTORC1) decreases bp(GO:"proteasome assembly") View Subject | View Object

Appears in Networks:

Evidence 828652e5d2
JSON

Tyrosine-protein kinase ABL1 is a proto- oncogene that negatively regulates autophagy, partly acting upstream of the RAC serine/threonine-protein kinase (AKT)–mTORC1 axis.

p(HGNC:ABL1) decreases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

Evidence 5695f0ca97
JSON

Activation of aquaporin 4 channels on perivascular astrocytes to aid the glymphatic elimination of cerebral Aβ and other toxic proteins is a potential strategy for stimulating clearance.

act(p(HGNC:AQP4)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:

Evidence 9e396cd025
JSON

However, in light of common risk genes such as SQSTM1 (which encodes p62) and chromosome 9 open reading frame 72 (C9ORF72), FTD is increasingly linked to ALS 82,83 .

p(HGNC:C9orf72) association path(MESH:"Frontotemporal Dementia") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Frontotemporal Dementia

p(HGNC:SQSTM1) association path(MESH:"Frontotemporal Dementia") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Frontotemporal Dementia

path(MESH:"Frontotemporal Dementia") association p(HGNC:SQSTM1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Frontotemporal Dementia

path(MESH:"Frontotemporal Dementia") association p(HGNC:C9orf72) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Frontotemporal Dementia

Evidence ffa57082c3
JSON

Mutations in C9ORF72 (the most prevalent risk gene for familial ALS and FTD) are likewise linked to disruption of the ALN, including interference with dynactin–dynein coordinated transport of autophagosomes along axons of motor neurons to the perikarya 82,88 .

p(HGNC:C9orf72, var("?")) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

Evidence 0426d9b52b
JSON

Genetic knockdown of calpain 1 or calpain 2 or overexpression of their endogenous inhibitor, calpastatin, increased autophagy and cleared aggregates in SK-N-SH cells overexpressing a mutant form of Htt 103 .

p(HGNC:CAPN1) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:CAPN1) decreases deg(p(HGNC:HTT, var("?"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:CAPN2) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:CAPN2) decreases deg(p(HGNC:HTT, var("?"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:CAST) decreases act(p(HGNC:CAPN1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:CAST) decreases act(p(HGNC:CAPN2)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:CAST) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:CAST) increases deg(p(HGNC:HTT, var("?"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

Evidence c441686683
JSON

Calpain inhibition by cal- pastatin or pharmacological agents also confers neuropro- tective effects in other NDA models, including improved clearance of tau, α-synuclein and SOD1 (REFS54,106,107) .

p(HGNC:CAST) increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

p(HGNC:CAST) increases deg(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

p(HGNC:CAST) increases deg(p(HGNC:SOD1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

Evidence 88dad808f4
JSON

ALS shares many causal genes with FTD, including SQSTM1, CHMP2B, TBK1 (which encodes tank-binding kinase 1), OPTN (which encodes optineurin) and other genes associated with deficits in ALN and mitophagy.

p(HGNC:CHMP2B) association path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

p(HGNC:OPTN) association path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

p(HGNC:SQSTM1) association path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

p(HGNC:TBK1) association path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

path(MESH:"Amyotrophic Lateral Sclerosis") association p(HGNC:SQSTM1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

path(MESH:"Amyotrophic Lateral Sclerosis") association p(HGNC:CHMP2B) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

path(MESH:"Amyotrophic Lateral Sclerosis") association p(HGNC:TBK1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

path(MESH:"Amyotrophic Lateral Sclerosis") association p(HGNC:OPTN) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

Evidence c656fe45fa
JSON

Other transcription factors that posi- tively regulate autophagy include forkhead box protein O1 (FOXO1) and FOXO3 (REF.22) .

p(HGNC:FOXO1) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

p(HGNC:FOXO3) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence 9fcf403b20
JSON

Fourth, homozygous mutations of lyso- somal β-glucocerebrosidase (βGCase; also known as GBA) provoke the LSD Gaucher disease, which is linked to decreased ALN flux, α-synuclein accumulation and a fivefold increase in risk of PD 43 (Supplementary Box 1).

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

Appears in Networks:
Annotations
MeSH
Parkinson Disease

p(HGNC:GBA, var("?")) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

p(HGNC:GBA, var("?")) increases a(HBP:HBP00016) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

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

Appears in Networks:
Annotations
MeSH
Parkinson Disease

Evidence aca74ea92d
JSON

Furthermore, expression of progranulin in the hippocampus of AD mice reduces the density of amyloid plaques by enhanc- ing the activity of neprilysin 281 .

p(HGNC:GRN) increases act(p(HGNC:MME)) View Subject | View Object

Appears in Networks:

p(HGNC:GRN) decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:

Evidence c69a9d6404
JSON

Aβ42 and amylin (a pancreas-derived, AD-associated protein found in brain) are substrates for degradation by IDE, which also irreversibly traps Aβ42 and α-synuclein, preventing their aggregation and promoting ALN and UPS elimination 259 .

p(HGNC:IDE) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:

p(HGNC:IDE) increases deg(p(HGNC:IAPP)) View Subject | View Object

Appears in Networks:

p(HGNC:IDE) decreases a(HBP:HBP00016) View Subject | View Object

Appears in Networks:

p(HGNC:IDE) decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:

Evidence 1574a8205b
JSON

IDE also degrades and prevents the forma- tion of α-synuclein fibrils 259 .

p(HGNC:IDE) decreases a(HBP:HBP00092) View Subject | View Object

Appears in Networks:

Evidence 4d02efdc38
JSON

Finally, the extracellular and intracellular serine protease neurosin (also known as KLK6) cleaves α- synuclein.

p(HGNC:KLK6) increases deg(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:

Evidence 2ab2ebca2b
JSON

Nonetheless, overexpression of LAMP2A accelerated CMA-related clearance of α-synuclein and afforded pro- tection of dopaminergic neurons 45 , and several routes to potential pharmacological exploitation exist.

p(HGNC:LAMP2) increases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Appears in Networks:

p(HGNC:LAMP2) increases deg(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:

Evidence 2ca01b27ca
JSON

Second, the GTPase leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) is the most commonly mutated protein in late-onset, familial PD.

p(HGNC:LRRK2, var("?")) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

path(MESH:"Parkinson Disease") association p(HGNC:LRRK2, var("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

Evidence cf72a67cf3
JSON

In addition, CMA is disrupted by sev- eral genetic mutations occurring in PD, including muta- tions in LRRK2 (REFS2,3,45–47,55,69,80) .

p(HGNC:LRRK2, var("?")) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

Evidence 178f1a75be
JSON

Similar to IDE, neprilysin catabolizes Aβ42, and its loss in mouse models of AD and in patients with AD alike also contributes to Aβ42 accumulation 253,256,260 .

p(HGNC:MME) increases deg(a(CHEBI:"amyloid-beta polypeptide 42")) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:MME) View Subject | View Object

Appears in Networks:

Evidence dd7c810a8c
JSON

For example, mutations in OPTN and TBK1 interfere with cargo loading 82,84,87 .

p(HGNC:OPTN, var("?")) decreases bp(GO:"cargo loading into vesicle") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

p(HGNC:TBK1, var("?")) decreases bp(GO:"cargo loading into vesicle") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

Evidence c91716b74e
JSON

First, autosomal recessive forms of early-onset PD are associated with mutations in PTEN-induced putative kinase protein 1 (PINK1) and the E3 ubiquitin-protein ligase parkin; these mutations lead to deficits in the mitophagic removal of damaged mitochondria 69,70 (BOX 2) .

p(HGNC:PINK1, var("?")) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

p(HGNC:PINK1, var("?")) decreases bp(GO:mitophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

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

Appears in Networks:
Annotations
MeSH
Parkinson Disease

p(HGNC:PRKN, var("?")) decreases bp(GO:mitophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

path(MESH:"Parkinson Disease") association p(HGNC:PINK1, var("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

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

Appears in Networks:
Annotations
MeSH
Parkinson Disease

Evidence 80b154482b
JSON

Like IDE and neprilysin, plasmin degrades Aβ42 and blocks Aβ42-induced toxicity, suggesting that the decrease in its levels in AD is involved in the evolution of AD 254,256,261 .

p(HGNC:PLG) increases deg(a(CHEBI:"amyloid-beta polypeptide 42")) View Subject | View Object

Appears in Networks:

Evidence 0670afa4e0
JSON

Plasmin also degrades α-synuclein to retard intercellular spreading 262 .

p(HGNC:PLG) increases deg(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:

Evidence fda632430d
JSON

Furthermore, mutations in the gene encoding parkin and several other genes are linked to reduced UPS activity 2,56,69,79,80 .

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

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

Evidence 1757b77227
JSON

Interestingly, genetic or pharmacological activation of RAB5 countered neurodegeneration in mouse C9ORF72 models of ALS and FTD 187 .

act(p(HGNC:RAB5A)) decreases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Amyotrophic Lateral Sclerosis
MeSH
Frontotemporal Dementia

Evidence 26bc6e63a9
JSON

Supporting the relevance of sestrin 2, it has been shown to protect dopaminergic neurons from the neurotoxin rotenone via AMPK-transduced autophagy 247 .

p(HGNC:SESN2) increases act(p(FPLX:AMPK)) View Subject | View Object

Appears in Networks:

p(HGNC:SESN2) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence f744b49d6b
JSON

Sestrin 2 over expression also prompted mTORC1-dependent autophagy in cortical neurons in a presenilin-knockout model of AD.

p(HGNC:SESN2) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 45b67644f6
JSON

Third, α-synuclein mutations, triplications or excesses amplify the ALN burden, interfere with auto phagosome formation and irreversibly disrupt the lysosomal mem- brane 1,3,44,56 .

p(HGNC:SNCA, var("?")) decreases bp(GO:"autophagosome assembly") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

p(HGNC:SNCA, var("?")) decreases a(GO:"lysosomal membrane") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parkinson Disease

Evidence 48eb990d0a
JSON

Conversely, repression is effected by signal transducer and activator of transcrip- tion 3 (STAT3) and possibly zinc-finger protein with KRAB and SCAN domains 3 (ZKSCAN3), although its role has been disputed 22,32 .

p(HGNC:STAT3) decreases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

p(HGNC:ZKSCAN3) decreases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence 0182fd3dc2
JSON

Unc-51-like kinase 1 (ULK1) is primarily an autophagy-initiating protein 3,10,19 , as is the mTORC1- suppressed transcrip- tion factor EB (TFEB), which orchestrates the synthesis of lysosomal and other proteins critical for maintaining ALN flux 20–23 .

p(HGNC:TFEB) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

p(HGNC:ULK1) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence aad7da9b2d
JSON

Indeed, TFEB over- expression reduced amyloid plaques in a APP/PS1 mouse model 148 .

p(HGNC:TFEB) decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

Evidence 0806b93dcb
JSON

Second, while decr1eases in beclin 1 levels in AD remain to be confirmed, SIRT1 expression is diminished 24 .

path(MESH:"Alzheimer Disease") decreases p(HGNC:SIRT1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence e9dfb7a488
JSON

ABL1 is overactivated in AD and tauopathies such as FTD 152 .

path(MESH:"Alzheimer Disease") increases act(p(HGNC:ABL1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

path(MESH:"Frontotemporal Dementia") increases act(p(HGNC:ABL1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

Evidence 5ca1153e9b
JSON

Cerebral levels of IDE are reduced in early AD and in mouse models of AD, whereas, mirroring AD amyloidosis, Aβ42 accumulates in mice genetically depleted of IDE.

path(MESH:"Alzheimer Disease") decreases p(HGNC:IDE) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrum

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.