The Ubiquitin Proteasome System as a Therapeutic Area in Parkinson's Disease.
Mitochondria
Mitophagy
Neurodegeneration
Parkin
Parkinson’s disease
Ubiquitin
Journal
Neuromolecular medicine
ISSN: 1559-1174
Titre abrégé: Neuromolecular Med
Pays: United States
ID NLM: 101135365
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
10
11
2022
accepted:
28
01
2023
medline:
22
9
2023
pubmed:
6
2
2023
entrez:
5
2
2023
Statut:
ppublish
Résumé
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD involves a combination of genetic and environmental factors. Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates mitochondrial dysfunction and protein aggregation. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, as well as the E3 ubiquitin ligase Parkin, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy. The ubiquitin proteasome system participates in several aspects of the cell's response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. This review examines the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes.
Identifiants
pubmed: 36739586
doi: 10.1007/s12017-023-08738-1
pii: 10.1007/s12017-023-08738-1
doi:
Substances chimiques
alpha-Synuclein
0
Proteasome Endopeptidase Complex
EC 3.4.25.1
Ubiquitin
0
Dopamine
VTD58H1Z2X
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
313-329Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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