Proteasomal function is impaired in substantia nigra in Parkinson’s disease
Abstract
The accumulation of alpha-synuclein, ubiquitin and other proteins in Lewy bodies in degenerating dopaminergic neurones in substantia nigra in idiopathic Parkinson's disease (PD) suggest that inhibition of normal/abnormal protein degradation may contribute to neuronal death. We now show for the first time that the chymotrypsin- (39%), trypsin- (42%) and postacidic-like (33%) hydrolysing activities of 20/26S proteasome are impaired in substantia nigra in PD. Proteasome inhibition does not appear to result from drug treatment since high concentrations of L-3,4-dihydroxyphenylalanine had no effect on enzymatic activity in vitro. These observations provide the first direct evidence that inhibition of the ubiquitin-proteasome pathway leading to altered protein handling and Lewy body formation may be responsible for degeneration of the nigrostriatal pathway in idiopathic PD.
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Failure of the ubiquitin-proteasome system in the substantia nigra in PD impairs degradation of α-synuclein, which facilitates formation of filamentous inclusions.
“the failure of the ubiquitin-proteasome system in the substantia nigra in PD [94] presumably impairs the degradation of α-synuclein, which facilitates the formation of filamentous inclusions.”
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 [94]
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 [94]
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 [94]
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- Authors
- McNaught, K. S. P., & Jenner, P.
- Affiliations
- King's College London (GB)
- Corresponding author
- Jenner, Peter
- ORCID
- Jenner, Peter
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2001-01
- Volume
- 297
- Issue
- 3
- Pages
- 191-194
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W2059737503
- Cited by
- 653
- References
- 20
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 19 · 2023: 23 · 2022: 18 · 2021: 25 · 2020: 26 · 2019: 10 · 2018: 25 · 2017: 19 · 2016: 16 · 2015: 25 · 2014: 21 · 2013: 26 · 2012: 20
- FWCI
- 35.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Parkinson's disease, proteasome, ubiquitin-proteasome system, substantia nigra, Lewy bodies, alpha-synuclein, dopaminergic neuron loss, proteasome inhibition, chymotrypsin-like activity, trypsin-like activity, L-DOPA, nigrostriatal pathway
- MeSH terms
- Acetylcysteine, Aged, Cysteine Endopeptidases, Dihydroxyphenylalanine, Enzyme Activation, Enzyme Inhibitors, Female, Humans, Hydrolysis, Levodopa, Male, Multienzyme Complexes, Parkinson Disease, Peptide Hydrolases, Protein Processing, Post-Translational, Substantia Nigra, Ubiquitins, Lewy Bodies, Proteasome Endopeptidase Complex
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