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

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

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.

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Acknowledgements

This study received funds as a scholarship from Mr. Martin Davis, a private donor. The funders had no role in study design, data collection and analysis, decision to publish, or the preparation of the manuscript.

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Authors and Affiliations

  1. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Micaela Johanna Glat & Daniel Offen

  2. Division of Neurobiology, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria

    Nadia Stefanova & Gregor Karl Wenning

  3. Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Daniel Offen

  4. Felsenstein Medical Research Center, Rabin Medical Center, 49100, Petha Tikva, Israel

    Daniel Offen

Authors
  1. Micaela Johanna Glat
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  2. Nadia Stefanova
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  3. Gregor Karl Wenning
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  4. Daniel Offen
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Contributions

Research project: MG, NS, GW and DO. Statistical analysis: MG. Manuscript: writing of the first draft—MG. Review and critique: GW, NS and DO. Intellectual property rights: DO and Tel Aviv University.

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Correspondence to Daniel Offen.

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Conflict of interest

DO and MG hold patents related to gene therapy in neurodegenerative diseases. NS and GW have nothing to disclose.

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Glat, M.J., Stefanova, N., Wenning, G.K. et al. Genes to treat excitotoxicity ameliorate the symptoms of the disease in mice models of multiple system atrophy. J Neural Transm 127, 205–212 (2020). https://doi.org/10.1007/s00702-020-02158-2

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  • DOI: https://doi.org/10.1007/s00702-020-02158-2

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