a(HBP:HBP00016)
Epigallocatechin-3-gallate (EGCG), a small molecule that been shown to inhibit the aggregation of several amyloidogenic proteins such as a-syn, amyloid-beta and huntingtin [9, 37, 38, 105] binds to unfolded native amyloid-beta and a-syn and promotes the formation of nontoxic oligomers that do not convert into amyloid fibrils [37]. PubMed:28803412
In vitro studies have shown that curcumin inhibited the formation of fibrils and disaggregated amyloid-beta and a-syn [112, 114, 155]. PubMed:28803412
Prabhudesai et al. showed that this molecule is able to inhibit the aggregation of a-syn in vitro and in a zebrafish model expressing human wild-type a-syn in neurons where CLR01 reduced apoptosis and improved embryo survival [127]. PubMed:28803412
The high proportion of cells with overlapping ChFP and ATTO-488 puncta (89 ± 7% upon cell exposure to 0.06 nM ATTO-488-labeled α -syn fibrils, Fig. 6f) indicates that α -syn fibrils seed with high efficiency the aggregation of soluble cytoplasmic ChFP-α -syn. PubMed:27075649
Prefibrillar oligomeric α -syn has been proposed to contribute to neurodegeneration by perturbing cellular ion homeostasis20, by seeding the assembly of soluble α -syn into higher molecular weight aggregates21, and/or by imbalancing cellular proteostasis22,23. PubMed:27075649
Parkinson’s disease (PD), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB) are devastating synucleinopathies. The deposition of filamentous insoluble protein inclusions termed Lewy bodies and Lewy neurites whose main constituent is aggregated α -synuclein (α -syn) characterizes synucleinopathies. PubMed:27075649
Parkinson’s disease (PD), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB) are devastating synucleinopathies. The deposition of filamentous insoluble protein inclusions termed Lewy bodies and Lewy neurites whose main constituent is aggregated α -synuclein (α -syn) characterizes synucleinopathies. PubMed:27075649
Parkinson’s disease (PD), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB) are devastating synucleinopathies. The deposition of filamentous insoluble protein inclusions termed Lewy bodies and Lewy neurites whose main constituent is aggregated α -synuclein (α -syn) characterizes synucleinopathies. PubMed:27075649
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 . PubMed:30116051
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 . PubMed:30116051
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) . PubMed:30116051
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 . PubMed:30116051
Among compounds that inhibit HSP90, geldanamycin promoted elimination of both hyper- phosphorylated tau and oligomeric α-synuclein in cell lines 219,220 . PubMed:30116051
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 . PubMed:30116051
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 . PubMed:30116051
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). PubMed:30116051
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 . PubMed:30116051
Not only did this discovery draw attention to aggregated forms of a-syn as mediators of Parkinson’s disease pathogenesis, but also opened the door to the use of a-syn detection techniques for diagnosis and staging. PubMed:28803412
Parkinson’s disease (PD), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB) are devastating synucleinopathies. The deposition of filamentous insoluble protein inclusions termed Lewy bodies and Lewy neurites whose main constituent is aggregated α -synuclein (α -syn) characterizes synucleinopathies. PubMed:27075649
Parkinson’s disease (PD), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB) are devastating synucleinopathies. The deposition of filamentous insoluble protein inclusions termed Lewy bodies and Lewy neurites whose main constituent is aggregated α -synuclein (α -syn) characterizes synucleinopathies. PubMed:27075649
Parkinson’s disease (PD), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB) are devastating synucleinopathies. The deposition of filamentous insoluble protein inclusions termed Lewy bodies and Lewy neurites whose main constituent is aggregated α -synuclein (α -syn) characterizes synucleinopathies. PubMed:27075649
Sixth, aggregates and mutant forms of α-synuclein disrupt the proteasome in dopaminergic neurons. PubMed:30116051
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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.