| First Author | McGlinchey RP | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 25 | Pages | 9973-9984 |
| PubMed ID | 31092553 | Mgi Jnum | J:281110 |
| Mgi Id | MGI:6368734 | Doi | 10.1074/jbc.RA119.008930 |
| Citation | McGlinchey RP, et al. (2019) C-terminal alpha-synuclein truncations are linked to cysteine cathepsin activity in Parkinson's disease. J Biol Chem 294(25):9973-9984 |
| abstractText | A pathological feature of Parkinson's disease (PD) is Lewy bodies (LBs) composed of alpha-synuclein (alpha-syn) amyloid fibrils. alpha-Syn is a 140 amino acids-long protein, but truncated alpha-syn is enriched in LBs. The proteolytic processes that generate these truncations are not well-understood. On the basis of our previous work, we propose that these truncations could originate from lysosomal activity attributable to cysteine cathepsins (Cts). Here, using a transgenic SNCA (A53T) mouse model, overexpressing the PD-associated alpha-syn variant A53T, we compared levels of alpha-syn species in purified brain lysosomes from nonsymptomatic mice with those in age-matched symptomatic mice. In the symptomatic mice, antibody epitope mapping revealed enrichment of C-terminal truncations, resulting from CtsB, CtsL, and asparagine endopeptidase. We did not observe changes in individual cathepsin activities, suggesting that the increased levels of C-terminal alpha-syn truncations are because of the burden of aggregated alpha-syn. Using LC-MS and purified alpha-syn, we identified C-terminal truncations corresponding to amino acids 1-122 and 1-90 from the SNCA (A53T) lysosomes. Feeding rat dopaminergic N27 cells with exogenous alpha-syn fibrils confirmed that these fragments originate from incomplete fibril degradation in lysosomes. We mimicked these events in situ by asparagine endopeptidase degradation of alpha-syn fibrils. Importantly, the resulting C-terminally truncated fibrils acted as superior seeds in stimulating alpha-syn aggregation compared with that of the full-length fibrils. These results unequivocally show that C-terminal alpha-syn truncations in LBs are linked to Cts activities, promote amyloid formation, and contribute to PD pathogenesis. |
