Viral-mediated oligodendroglial alpha-synuclein expression models multiple system atrophy.
Mov Disord.. 2017-05-29; 32(8): 1230-1239
DOI: 10.1002/mds.27041
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1. Mov Disord. 2017 Aug;32(8):1230-1239. doi: 10.1002/mds.27041. Epub 2017 May 29.
Viral-mediated oligodendroglial alpha-synuclein expression models multiple system
atrophy.
Bassil F(1)(2), Guerin PA(1)(2), Dutheil N(1)(2), Li Q(3)(4), Klugmann M(5),
Meissner WG(1)(2)(6)(7), Bezard E(1)(2)(3)(4), Fernagut PO(1)(2).
Author information:
(1)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
Bordeaux, France.
(2)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
(3)China Academy of Medical Sciences, Institute of Lab Animal Sciences, Beijing,
China.
(4)Motac neuroscience Ltd, Manchester, United Kingdom.
(5)Translational Neuroscience Facility and Department of Physiology, School of
Medical Sciences, UNSW Australia, Sydney, NSW, Australia.
(6)Service de Neurologie, CHU de Bordeaux, Bordeaux, France.
(7)Centre de référence atrophie multisystématisée, CHU de Bordeaux, Bordeaux,
France.
BACKGROUND: MSA is a fatal neurodegenerative disorder characterized by a
combination of autonomic dysfunction, cerebellar ataxia, and l-dopa unresponsive
parkinsonism. The hallmark of MSA is the accumulation of α-synuclein, forming
cytoplasmic inclusions in oligodendrocytes. Adeno-associated viruses allow
efficient targeting of disease-associated genes in selected cellular ensembles
and have proven efficient for the neuronal overexpression of α-synuclein in the
substantia nigra in the context of PD.
OBJECTIVES: We aimed to develop viral-based models of MSA.
METHODS: Chimeric viral vectors expressing either human wild-type α-synuclein or
green fluorescent protein under the control of mouse myelin basic protein were
injected in the striatum of rats and monkeys. Rats underwent a longitudinal motor
assessment before histopathological analysis at 3 and 6 months.
RESULTS: Injection of vectors expressing α-synuclein in the striatum resulted in
>80% oligodendroglial selectivity in rats and >60% in monkeys. Rats developed
progressive motor deficits that were l-dopa unresponsive when assessed at 6
months. Significant loss of dopaminergic neurons occurred at 3 months, further
progressing at 6 months, together with a loss of striatal neurons. Prominent
α-synuclein accumulation, including phosphorylated and proteinase-K-resistant
α-synuclein, was detected in the striatum and substantia nigra.
CONCLUSIONS: Viral-mediated oligodendroglial expression of α-synuclein allows
replicating some of the key features of MSA. This flexible strategy can be used
to investigate, in several species, how α-synuclein accumulation in selected
oligodendroglial populations contributes to the pathophysiology of MSA and offers
a new framework for preclinical validation of therapeutic strategies. © 2017
International Parkinson and Movement Disorder Society.
© 2017 International Parkinson and Movement Disorder Society.
DOI: 10.1002/mds.27041
PMID: 28556404 [Indexed for MEDLINE]