Genes to treat excitotoxicity ameliorate the symptoms of the disease in mice models of multiple system atrophy

J Neural Transm (Vienna). 2020 Feb;127(2):205-212. doi: 10.1007/s00702-020-02158-2. Epub 2020 Feb 17.


Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterized by striatonigral degeneration and olivopontocerebellar atrophy. The main hallmark of MSA is the aggregation of alpha-synuclein in oligodendrocytes, which contributes to the dysfunction and death of the oligodendrocytes, followed by neurodegeneration. Studies suggested that oxidative-excitatory pathway is associated with the progression of the disease. The aim of the current study was to test this concept by overexpression of excitatory amino acid transporter 2, glutamate dehydrogenase and nuclear factor (erythroid-derived 2)-related factor 2 genes in the striatum of two established mouse models of MSA. To induce the first model, we injected the mitochondrial neurotoxin, 3-nitropropionic acid (3-NP), unilaterally into the right striatum in 2-month-old C57BL/6 male mice. We demonstrate a significant improvement in two drug-induced rotational behavior tests, following unilateral injection the three genes. For the second model, we used transgenic mice expressing the alpha-synuclein gene under the proteolipid protein, in the age of 7 months, boosted with 3-NP to enhance the motor deficits and neurodegeneration. We show that the overexpression of the three genes attenuated the motor-related deficit in the elevated bridge and pole tests. Thus, our study indicates that glutamate excito-oxidative toxicity plays a major role in this MSA model and our gene therapy approach might suggest a novel strategy for MSA treatment.

Keywords: Excitotoxicity; Gene therapy; Multiple system atrophy; Neuroprotection; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology*
  • Convulsants / administration & dosage
  • Corpus Striatum / drug effects
  • Disease Models, Animal*
  • Excitatory Amino Acid Transporter 2 / genetics
  • Genetic Therapy*
  • Glutamate Dehydrogenase / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Multiple System Atrophy / physiopathology*
  • Multiple System Atrophy / therapy*
  • NF-E2-Related Factor 2 / genetics
  • Nitro Compounds / administration & dosage
  • Propionates / administration & dosage


  • Convulsants
  • Excitatory Amino Acid Transporter 2
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nitro Compounds
  • Propionates
  • SLC1A2 protein, human
  • Glutamate Dehydrogenase
  • 3-nitropropionic acid