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Cited by 305Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsLysosomal Storage Disorders Research

Cathepsin D Is the Main Lysosomal Enzyme Involved in the Degradation of α-Synuclein and Generation of Its Carboxy-Terminally Truncated Species

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Sevlever, Daniel, Jiang, Peizhou, Yen, Shu-Hui C.·2008·Biochemistry
DOI 10.1021/bi800699vPMC PMC2630205
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Abstract

Alpha-synuclein is likely to play a key role in the development of Parkinson's disease as well as other synucleinopathies. In animal models, overexpression of full-length or carboxy-terminally truncated alpha-synuclein has been shown to produce pathology. Although the proteosome and lysosome have been proposed to play a role in the degradation of alpha-synuclein, the enzyme(s) involved in alpha-synuclein clearance and generation of its carboxy-terminally truncated species have not been identified. In this study, the role of cathepsin D and calpain I in these processes was analyzed. In vitro experiments, using either recombinant or endogenous alpha-synuclein as substrates and purified cathepsin D or lysosomes, demonstrated that cathepsin D degraded alpha-synuclein very efficiently, and that limited proteolysis resulted in the generation of carboxy-terminally truncated species. Purified calpain I also cleaved alpha-synuclein, but carboxy-terminally truncated species were not the main cleavage products, and calpain I activity present in cellular lysates was not able to degrade the protein. Knockdown of cathepsin D in cells overexpressing wild-type alpha-synuclein increased total alpha-synuclein levels by 28% and lysosomal alpha-synuclein by 2-fold. In in vitro experiments, pepstatin A completely blocked the degradation of alpha-synuclein in purified lysosomes. Furthermore, lysosomes isolated from cathepsin D knockdown cells showed a marked reduction in alpha-synuclein degrading activity, indicating that cathepsin D is the main lysosomal enzyme involved in alpha-synuclein degradation. Our findings suggest that upregulation of cathepsin D could be an additional therapeutic strategy to lessen alpha-synuclein burden in synucleinopathies.

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  • CTSD is considered a key protease in the lysosomal degradation of many pathogenic proteins in addition to APP metabolites, including α-synuclein and huntingtin.

    “CTSD is considered as a key protease in the lysosomal degradation of many pathogenic proteins in addition to APP metabolites, including ␣-synuclein and huntingtin (Kegel et al., 2000;Sevlever et al., 2008).”

    From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Sevlever et al., 2008

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Authors
Sevlever, D., Jiang, P., & Yen, S.-H. C.
Affiliations
  • Mayo Clinic (US)
  • Mayo Clinic in Florida (US)
Corresponding author
Sevlever, Daniel
ORCID
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2008-08-15
Volume
47
Issue
36
Pages
9678-9687
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi800699v
PMC
PMC2630205
OpenAlex
W2022649483
Cited by
305
References
30
Citations by year
2026: 7 · 2025: 17 · 2024: 17 · 2023: 23 · 2022: 16 · 2021: 20 · 2020: 34 · 2019: 15 · 2018: 14 · 2017: 19 · 2016: 20 · 2015: 19 · 2014: 19 · 2013: 16 · 2012: 13
FWCI
7.49
Type
journal article
Language
en
Open access
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Mayo Clinic
  • National Institute of Neurological Disorders and Stroke (P50-NS40256, P50NS040256)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
alpha-synuclein, cathepsin D, calpain-1, lysosomal degradation, Parkinson's disease, synucleinopathies, pepstatin A, limited proteolysis, lysosomal enzymes
MeSH terms
Animals, Calpain, Cathepsin D, Disease Models, Animal, Humans, Lysosomes, Parkinson Disease, Gene Deletion, Cell Line, Tumor, Mice, alpha-Synuclein

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