Viral-mediated oligodendroglial alpha-synuclein expression models multiple system atrophy

Mov Disord. 2017 Aug;32(8):1230-1239. doi: 10.1002/mds.27041. Epub 2017 May 29.


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.

Keywords: alpha-synuclein; animal model; multiple system atrophy; oligodendrocytes; rat.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Dopamine Agents / therapeutic use
  • Gene Expression Regulation / genetics*
  • Haplorhini
  • Humans
  • Levodopa / therapeutic use
  • Male
  • Multiple System Atrophy / etiology
  • Multiple System Atrophy / genetics*
  • Multiple System Atrophy / pathology*
  • Myelin Basic Protein / immunology
  • Nerve Tissue Proteins / metabolism
  • Oligodendroglia / metabolism*
  • Phosphorylation / genetics
  • Psychomotor Performance / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • Dopamine Agents
  • Myelin Basic Protein
  • Nerve Tissue Proteins
  • alpha-Synuclein
  • Levodopa