&amp;#945;-Synuclein Misfolding and Neurodegenerative Diseases

Uversky, Vladimir N.

doi:10.2174/138920308785915218

Cited by 182 publications

(168 citation statements)

References 430 publications

(799 reference statements)

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“…Proposed mechanisms include impaired protein degradation (both UPS and autophagy), toxicity to synaptic terminals, inflammation, and induction of mitochondrial dysfunction [39]. Although α-syn fibrils have been found in both humans and animal models of synucleinopathies, several lines of evidence suggest that nonfibrillar soluble oligomers of α-syn are the most toxic species [40,41].…”

Section: Discussionmentioning

confidence: 99%

A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo

et al. 2012

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Section: Discussionmentioning

confidence: 99%

A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo

et al. 2012

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“…A primary cause leading to PD is associated with impaired α-syn turnover (11)(12)(13). Hence, boosting the degradation of α-syn could be an effective way to alleviate this burden.…”

Section: Protein-lipid Interactionsmentioning

confidence: 99%

Cysteine cathepsins are essential in lysosomal degradation of α-synuclein

McGlinchey

Lee

2015

Proc. Natl. Acad. Sci. U.S.A.

185

180

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A cellular feature of Parkinson’s disease is cytosolic accumulation and amyloid formation of α-synuclein (α-syn), implicating a misregulation or impairment of protein degradation pathways involving the proteasome and lysosome. Within lysosomes, cathepsin D (CtsD), an aspartyl protease, is suggested to be the main protease for α-syn clearance; however, the protease alone only generates amyloidogenic C terminal-truncated species (e.g., 1–94, 5–94), implying that other proteases and/or environmental factors are needed to facilitate degradation and to avoid α-syn aggregation in vivo. Using liquid chromatography–mass spectrometry, to our knowledge, we report the first peptide cleavage map of the lysosomal degradation process of α-syn. Studies of purified mouse brain and liver lysosomal extracts and individual human cathepsins demonstrate a direct involvement of cysteine cathepsin B (CtsB) and L (CtsL). Both CtsB and CtsL cleave α-syn within its amyloid region and circumvent fibril formation. For CtsD, only in the presence of anionic phospholipids can this protease cleave throughout the α-syn sequence, suggesting that phospholipids are crucial for its activity. Taken together, an interplay exists between α-syn conformation and cathepsin activity with CtsL as the most efficient under the conditions examined. Notably, we discovered that CtsL efficiently degrades α-syn amyloid fibrils, which by definition are resistant to broad spectrum proteases. This work implicates CtsB and CtsL as essential in α-syn lysosomal degradation, establishing groundwork to explore mechanisms to enhance their cellular activity and levels as a potential strategy for clearance of α-syn.

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“…These expanded proteins are often misfolded and accumulate in insoluble polymers, 1,2 and eventually form fibrillar structures. 3 In addition to the disease-associated protein aggregation, widespread protein aggregation was recently found in normal aging of C. elegans. 4 Common to the polyGlu or polyAla and the aging-associated aggregated proteins is that they are found in a broad spectrum of cell types.…”

Section: Introductionmentioning

confidence: 99%