The good and bad of therapeutic strategies that directly target α-synuclein.
small molecule inhibitors of protein aggregation
synucleinopathies
α-Synuclein
α-Synuclein gene silencing
α-Synuclein immunotherapy
α-Synuclein pathology
Journal
IUBMB life
ISSN: 1521-6551
Titre abrégé: IUBMB Life
Pays: England
ID NLM: 100888706
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
29
08
2019
accepted:
12
10
2019
pubmed:
7
11
2019
medline:
22
6
2021
entrez:
7
11
2019
Statut:
ppublish
Résumé
Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α-synuclein (α-syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α-syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α-syn pathology. This poses the question of which is the most toxic α-syn species. What is worst, α-syn appears as a very peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α-helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α-syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or overexpression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α-syn levels, oligomer formation, fibrillation, or cell-to-cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α-syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state-of-the-art α-syn biology.
Substances chimiques
Intermediate Filament Proteins
0
alpha-Synuclein
0
desmuslin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
590-600Informations de copyright
© 2019 International Union of Biochemistry and Molecular Biology.
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