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Cysteine cathepsins are essential in lysosomal degradation of α-synuclein

Author:
McGlinchey, Ryan P., Lee, Jennifer C.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.30 pp. 9322-9327
ISSN:
0027-8424
Subject:
Parkinson disease, amyloid, cathepsin L, cysteine, etiology, lipid metabolism, lysosomes, mass spectrometry, mice, pathogenesis, peptide mapping, phospholipids, proteolysis
Abstract:
Identifying factors that regulate the degradation of α-synuclein, the protein at the center of Parkinson’s disease etiology, is vital in designing therapeutic strategies. This study provides new mechanistic insights into α-synuclein clearance in the lysosome, a cellular site for proteolysis by using purified mouse lysosomes and purified lysosomal proteases. Cathepsins B and L are identified to be vital through peptide mapping by mass spectrometry. Importantly, cathepsin L degrades α-synuclein amyloid fibrils, materials associated with neurodegeneration, and, thus, changes in its activity or levels could provide a promising avenue for intervention. Additional results on the stimulatory effect of anionic phospholipids on cathepsin activity suggest that changes in lipid metabolism may also contribute to lysosomal dysfunction leading to pathogenesis.
Agid:
3387243