Cited by 167Alzheimer's disease research and treatmentsProtease and Inhibitor MechanismsLysosomal Storage Disorders Research

The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders

Vidoni, Chiara, Follo, Carlo, Savino, Miriam, Melone, Mariarosa A. B., Isidoro, Ciro·2016·Medicinal Research Reviews

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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Crossref · 10.1002/med.21394

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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).”
  • 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).”

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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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