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

Micaela Johanna Glat, Nadia Stefanova, Gregor Karl Wenning, Daniel Offen

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)205-212
Number of pages8
JournalJournal of Neural Transmission
Issue number2
StatePublished - 1 Feb 2020


  • Excitotoxicity
  • Gene therapy
  • Multiple system atrophy
  • Neuroprotection
  • Oxidative stress

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry


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