ß-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins.
J Biol Chem
; 297(6): 101375, 2021 12.
Article
em En
| MEDLINE
| ID: mdl-34736896
ABSTRACT
Synucleins, a family of three proteins highly expressed in neurons, are predominantly known for the direct involvement of α-synuclein in the etiology and pathogenesis of Parkinson's and certain other neurodegenerative diseases, but their precise physiological functions are still not fully understood. Previous studies have demonstrated the importance of α-synuclein as a modulator of various mechanisms implicated in chemical neurotransmission, but information concerning the involvement of other synuclein family members, ß-synuclein and γ-synuclein, in molecular processes within presynaptic terminals is limited. Here, we demonstrated that the vesicular monoamine transporter 2-dependent dopamine uptake by synaptic vesicles isolated from the striatum of mice lacking ß-synuclein is significantly reduced. Reciprocally, reintroduction, either in vivo or in vitro, of ß-synuclein but not α-synuclein or γ-synuclein improves uptake by triple α/ß/γ-synuclein-deficient striatal vesicles. We also showed that the resistance of dopaminergic neurons of the substantia nigra pars compacta to subchronic administration of the Parkinson's disease-inducing prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine depends on the presence of ß-synuclein but only when one or both other synucleins are absent. Furthermore, proteomic analysis of synuclein-deficient synaptic vesicles versus those containing only ß-synuclein revealed differences in their protein compositions. We suggest that the observed potentiation of dopamine uptake by ß-synuclein might be caused by different protein architecture of the synaptic vesicles. It is also feasible that such structural changes improve synaptic vesicle sequestration of 1-methyl-4-phenylpyridinium, a toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which would explain why dopaminergic neurons expressing ß-synuclein and lacking α-synuclein and/or γ-synuclein are resistant to this neurotoxin.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vesículas Sinápticas
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Dopamina
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1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina
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Morte Celular
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Beta-Sinucleína
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Neurônios Dopaminérgicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article