The intracellular accumulation of alpha-synuclein (alpha-syn) amyloid fibrils is a hallmark of Parkinson's disease. Because lysosomes are responsible for degrading aggregated species, enhancing lysosomal function could alleviate the overburden of alpha-syn. Previously, we showed that cysteine cathepsins (Cts) is the main class of lysosomal proteases that degrade alpha-syn, and in particular, CtsL was found to be capable of digesting alpha-syn fibrils. Here, we report that CtsK is a more potent protease for degrading alpha-syn amyloids. Using peptide mapping by liquid chromatography with mass spectrometry, critical cleavage sites involved in destabilizing fibril structure are identified. CtsK is only able to devour the internal regions after the removal of both N- and C-termini, indicating their protective role of the amyloid core from proteolytic attack. Our results suggest that if overexpressed in lysosomes, CtsK has the potential to ameliorate alpha-syn pathology. Published by Elsevier Inc.