The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders
Abstract
In familial neurodegenerative disorders, protein aggregates form continuously because of genetic mutations that drive the synthesis of truncated or unfolded proteins. The oxidative stress imposed by neurotransmitters and environmental neurotoxins constitutes an additional threat to the folding of the proteins and the integrity of organelle membranes in neurons. Failure in degrading such altered materials compromises the function of neurons and eventually leads to neurodegeneration. The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease ubiquitously expressed in all the cells of the human body, and it is expressed at high level in the brain. In general, cathepsin D mediated proteolysis is essential to neuronal cell homeostasis through the degradation of unfolded or oxidized protein aggregates delivered to lysosomes via autophagy or endocytosis. More specifically, many altered neuronal proteins that hallmark neurodegenerative diseases (e.g., the amyloid precursor, α-synuclein, and huntingtin) are physiologic substrates of cathepsin D and would abnormally accumulate if not efficiently degraded by this enzyme. Furthermore, experimental evidence indicates that cathepsin D activity is linked to the metabolism of cholesterol and of glycosaminoglycans, which accounts for its involvement in neuronal plasticity. This review focuses on the unique role of cathepsin D mediated proteolysis in the pathogenesis of human neurodegenerative diseases.
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CTSD activation is deficient in various neuropathologic states and as a result of genetic mutations.
“CTSD activation is deficient in various neuropathologic states and as a result of genetic mutations (Colacurcio and Nixon, 2016;Vidoni et al., 2016).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Vidoni et al., 2016
The findings support an emerging concept that acidification impairment may be a proximal biochemical event in AD, common to multiple genetic risk factors that cause or promote AD.
“The findings support an emerging concept that acidification impairment may be a proximal biochemical event in AD, common to multiple genetic risk factors that cause or promote AD (Lee et al., 2010;Xue et al., 2014;Vidoni et al., 2016).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Vidoni et al., 2016
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- Authors
- Vidoni, C., Follo, C., Savino, M., Melone, M. A. B., & Isidoro, C.
- Affiliations
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Corresponding author
- Isidoro, Ciro
- Venue
- Medicinal Research Reviews
- Publisher
- Wiley
- Published
- 2016-04-26
- Volume
- 36
- Issue
- 5
- Pages
- 845-870
- ISSN
- 0198-6325 (ISSN-L)
- 1098-1128
- OpenAlex
- W2342739937
- Cited by
- 164
- References
- 201
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 18 · 2023: 21 · 2022: 16 · 2021: 24 · 2020: 13 · 2019: 14 · 2018: 9 · 2017: 13 · 2016: 2
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Medicinal Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- University of California San Francisco
- Ministry of Education
- MIUR (20109MXHMR_004)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- cathepsin D, neurodegenerative diseases, protein aggregation, lysosomal proteolysis, aspartic protease, autophagy, endocytosis, amyloid precursor protein, alpha-synuclein, huntingtin, oxidative stress, cholesterol metabolism, glycosaminoglycans, neuroplasticity
- MeSH terms
- Animals, Cathepsin D, Humans, Neurodegenerative Diseases
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