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An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

Gene Therapy volume 11, pages 1713–1723 (2004)Cite this article

Abstract

Current experimental gene therapy approaches for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) include the use of viral vectors expressing antiapoptosis genes, neurotrophic factors and dopaminergic system enzymes. However, since increasing evidence favors a role for α-synuclein accumulation in the pathogenesis of these disorders, an alternative therapy might require the transfer of genes that might block α-synuclein accumulation. β-Synuclein, the nonamyloidogenic homologue of α-synuclein, has recently been identified as a potential candidate. Thus, in vivo transfer of genes encoding β-synuclein might provide a novel approach to the development of experimental treatments for PD and DLB. To assess this possibility and to better understand the mechanisms involved, a lentiviral vector expressing human (h) β-synuclein (lenti-β-synuclein) was tested in a transgenic (tg) mouse model of hα-synuclein aggregation. This study showed that unilateral intracerebral injection of lenti-β-synuclein reduced the formation of hα-synuclein inclusions and the accumulation of hα-synuclein in synapses and ameliorated the neurodegenerative alterations in the tg mice. Both in vivo and in vitro coimmunoprecipitation and immunoblot experiments show that the mechanisms of β-synuclein neuroprotection involve binding of this molecule to hα-synuclein and Akt, resulting in the decreased aggregation and accumulation of hα-synuclein in the synaptic membrane. Together, these data further support a role for β-synuclein in regulating the conformational state of α-synuclein and suggest that this gene transfer approach might have potential for the development of alternative therapies for PD and DLB.

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Acknowledgements

This work was supported by National Institutes of Health Grants AG5131, and AG18440 and by a grant from the MJ Fox Foundation for Parkinson's Research to EM and by AG08514 to FHG. RAM was supported in part by funds from the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    M Hashimoto, E Rockenstein, M Mante, L Crews, P Bar-On & E Masliah

  2. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA

    FH Gage & R Marr

  3. Department of Pathology, University of California, San Diego, La Jolla, CA, USA

    E Masliah

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Hashimoto, M., Rockenstein, E., Mante, M. et al. An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model. Gene Ther 11, 1713–1723 (2004). https://doi.org/10.1038/sj.gt.3302349

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