The presynaptic protein, α-synuclein (α-syn), is a central player in Parkinson’s disease (PD). A primary cause of cellular dysfunction is associated with impaired α-synuclein (α-syn) turnover, leading to the cytosolic accumulation of α-syn amyloid fibrils. Understanding cellular mechanisms of maintaining α-syn homeostasis is critical in establishing ways to circumvent the progression of PD. In our work, we have gained mechanistic insights into α-syn clearance in the lysosome, a cellular site responsible for removal of insoluble and aggregated species. Using liquid chromatography-mass spectrometry, the complete degradation process of α-syn in lysosomal extracts has been peptide mapped and assigned to individual lysosomal cathepsins (Cts). We identified CtsB and CtsL as essential for lysosomal degradation of α-syn, cleaving within its amyloid region and circumvent fibril formation. Unexpectedly, we discovered that CtsL is efficient in degrading α-syn amyloid fibrils, which by definition are resistant to broad spectrum proteases. Based on the potency of CtsL towards α-syn amyloid fibrils, we are currently examining the effect of CtsL activity on the clearance of exogenously added fibrils in a rat dopaminergic neuronal N27 cell line, testing the hypothesis that enhancement of CtsL cellular activity will ameliorate the burden of α-syn load in a cell.

Role of cathepsin L in α-synuclein degradation

255th National Meeting (2018)

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