期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 30, 页码 9322-9327出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1500937112
关键词
amyloid; Parkinson's disease; mass spectrometry; lysosomes; protein-lipid interactions
资金
- National Institutes of Health, NHLBI
A cellular feature of Parkinson's disease is cytosolic accumulation and amyloid formation of a-synuclein (alpha-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 alpha-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 alpha-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 alpha-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 alpha-syn within its amyloid region and circumvent fibril formation. For CtsD, only in the presence of anionic phospholipids can this protease cleave throughout the alpha-syn sequence, suggesting that phospholipids are crucial for its activity. Taken together, an interplay exists between alpha-syn conformation and cathepsin activity with CtsL as the most efficient under the conditions examined. Notably, we discovered that CtsL efficiently degrades alpha-syn amyloid fibrils, which by definition are resistant to broad spectrum proteases. This work implicates CtsB and CtsL as essential in alpha-syn lysosomal degradation, establishing groundwork to explore mechanisms to enhance their cellular activity and levels as a potential strategy for clearance of alpha-syn.
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