Imperial College London
Professor Dominic Withers

ProfessorDominicWithers

Faculty of Medicine, Institute of Clinical Sciences

Clinical Chair in Diabetes & Endocrinology
 
 
 
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Contact

 

d.withers

 
 
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Location

 

Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ninkina:2021:10.1016/j.jbc.2021.101375,
author = {Ninkina, N and Millership, SJ and Peters, OM and Connor-Robson, N and Chaprov, K and Kopylov, AT and Montoya, A and Kramer, H and Withers, DJ and Buchman, VL},
doi = {10.1016/j.jbc.2021.101375},
journal = {Journal of Biological Chemistry},
pages = {1--15},
title = {β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins.},
url = {http://dx.doi.org/10.1016/j.jbc.2021.101375},
volume = {297},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Synucleins, a family of three proteins highly expressed in neurons, are predominantly known for the direct involvement of α-synuclein in the aetiology 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, β-synuclein and γ-synuclein, in molecular processes within presynaptic terminals is limited. Here we demonstrated that the vesicular monoamine transporter 2 (VMAT2)-dependent dopamine uptake by synaptic vesicles isolated from the striatum of mice lacking β-synuclein is significantly reduced. Reciprocally, reintroduction, either in vivo or in vitro, of β-synuclein but not α- or γ-synuclein improves uptake by triple α/β/γ-synuclein deficient striatal vesicles. We also showed that the resistance of dopaminergic neurons of the substantia nigra pars compacta (SNpc) to subchronic administration of the Parkinson's disease-inducing prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) depends on the presence of β-synuclein but only when one or both other synucleins are absent. Furthermore, proteomic analysis of synuclein-deficient synaptic vesicles vs those containing only β-synuclein revealed differences in their protein compositions. We suggest that the observed potentiation of dopamine uptake by β-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 (MPP+), a toxic metabolite of MPTP, which would explain why dopaminergic neurons expressing β-synuclein and lacking α-synuclein and/or γ-synuclein are resistant t
AU  - Ninkina,N
AU  - Millership,SJ
AU  - Peters,OM
AU  - Connor-Robson,N
AU  - Chaprov,K
AU  - Kopylov,AT
AU  - Montoya,A
AU  - Kramer,H
AU  - Withers,DJ
AU  - Buchman,VL
DO  - 10.1016/j.jbc.2021.101375
EP  - 15
PY  - 2021///
SN  - 0021-9258
SP  - 1
TI  - β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins.
T2  - Journal of Biological Chemistry
UR  - http://dx.doi.org/10.1016/j.jbc.2021.101375
UR  - https://www.ncbi.nlm.nih.gov/pubmed/34736896
UR  - https://www.sciencedirect.com/science/article/pii/S0021925821011819?via%3Dihub
UR  - http://hdl.handle.net/10044/1/92795
VL  - 297
ER  -
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