Proteolytic stress: A unifying concept for the etiopathogenesis of Parkinson’s disease
Abstract
The etiopathogenesis of Parkinson's disease (PD) has been elusive. Recently, several lines of evidence have converged to suggest that defects in the ubiquitin-proteasome system and proteolytic stress underlie nigral pathology in both familial and sporadic forms of the illness. In support of this concept, mutations in alpha-synuclein that cause the protein to misfold and resist proteasomal degradation cause familial PD. Similarly, mutations in two enzymes involved in the normal function of the ubiquitin-proteasome system, parkin and ubiquitin C-terminal hydrolase L1, are also associated with hereditary PD. Furthermore, structural and function defects in 26/20S proteasomes with accumulation and aggregation of potentially cytotoxic abnormal proteins have been identified in the substantia nigra pars compacta of patients with sporadic PD. Thus, a defect in protein handling appears to be a common factor in sporadic and the various familial forms of PD. This hypothesis may also account for the vulnerability of the substantia nigra pars compacta in PD, why the disorder is age related, and the nature of the Lewy body. It has also facilitated the development of experimental models that recapitulate the behavioral and pathological features of PD, and hopefully will lead to the development of novel neuroprotective therapies for the disorder.
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Reduction of proteasomal activity in PD supports the accumulation of pSer40-TH to form inclusion bodies in PD patients.
“Insight into the reduction of proteasomal activity in PD [94,95,96] further supports the evidence of the accumulation of pSer40-TH to form inclusion bodies in PD patients [71].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [96]
Failure of the ubiquitin-proteasome system is implicated in the pathogenesis of both sporadic and familial PD.
“Failure of the ubiquitin-proteasome system is implicated in the pathogenesis of both sporadic and familial PD [22,23,24,94,95,96].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [96]
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- Authors
- McNaught, K. S. P., & Olanow, C. W.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Olanow, C. Warren
- ORCID
- Olanow, C. Warren
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2003
- Volume
- 53
- Issue
- S3
- Pages
- S73-S86
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2135387829
- Cited by
- 203
- References
- 96
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 2 · 2021: 2 · 2020: 7 · 2019: 1 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 5 · 2013: 3 · 2012: 6
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns033772-09)
- National Institute of Neurological Disorders and Stroke (NS 33772)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Parkinson's disease, ubiquitin-proteasome system, alpha-synuclein, Parkin, UCHL1, substantia nigra pars compacta, Lewy bodies, familial Parkinson's disease, sporadic Parkinson's disease, protein aggregation, neuroprotection
- MeSH terms
- Cysteine Endopeptidases, Humans, Ligases, Multienzyme Complexes, Nerve Degeneration, Nerve Tissue Proteins, Parkinson Disease, Peptide Hydrolases, Substantia Nigra, Thiolester Hydrolases, Lewy Bodies, Point Mutation, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Synucleins, alpha-Synuclein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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