Viral-Mediated Oligodendroglial Alpha-Synuclein Expression Models Multiple System Atrophy

被引：36
作者：
Bassil, Fares [1 ,2 ]
Guerin, Paul A. [1 ,2 ]
Dutheil, Nathalie [1 ,2 ]
Li, Qin [3 ,4 ]
Klugmann, Matthias [5 ,6 ]
Meissner, Wassilios G. [1 ,2 ,7 ,8 ]
Bezard, Erwan [1 ,2 ,3 ,4 ]
Fernagut, Pierre-Olivier [1 ,2 ]
机构：
[1] Univ Bordeaux, Inst Malad Neurodegenerat, UMR 5293, Bordeaux, France
[2] CNRS, Inst Malad Neurodegenerat, UMR 5293, Bordeaux, France
[3] China Acad Med Sci, Inst Lab Anim Sci, Beijing, Peoples R China
[4] Motac Neurosci Ltd, Manchester, Lancs, England
[5] UNSW Australia, Translat Neurosci Facil, Sydney, NSW, Australia
[6] UNSW Australia, Dept Physiol, Sch Med Sci, Sydney, NSW, Australia
[7] CHU Bordeaux, Serv Neurol, Bordeaux, France
[8] CHU Bordeaux, Ctr Reference Atrophie Multisystematisee, Bordeaux, France
来源：
MOVEMENT DISORDERS | 2017年 / 32卷 / 08期
关键词：
multiple system atrophy; oligodendrocytes; alpha-synuclein; rat; animal model; TRANSGENIC MOUSE MODEL; CYTOPLASMIC INCLUSIONS; PARKINSONS-DISEASE; BRAIN; INVOLVEMENT; DYSFUNCTION; PREVALENCE; DYSKINESIA; DEPLETION; SPECTRUM;
D O I：
10.1002/mds.27041
中图分类号：
R74 [神经病学与精神病学];
学科分类号：
摘要：
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 alpha-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 alpha-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 alpha-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 alpha-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 alpha-synuclein accumulation, including phosphorylated and proteinase-K-resistant alpha-synuclein, was detected in the striatum and substantia nigra. Conclusions: Viral-mediated oligodendroglial expression of alpha-synuclein allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how alpha-synuclein accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for preclinical validation of therapeutic strategies. (C) 2017 International Parkinson and Movement Disorder Society
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收藏
页码：1230 / 1239
页数：10
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