An antiaggregation gene therapy strategy for Lewy body disease utilizing beta-synuclein lentivirus in a transgenic
M Hashimoto1, E Rockenstein, M Mante
1Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA.
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 alpha-synuclein accumulation in the pathogenesis of these disorders, an alternative therapy might require the transfer of genes that might block alpha-synuclein accumulation. beta-Synuclein, the nonamyloidogenic homologue of alpha-synuclein, has recently been identified as a potential candidate. Thus, in vivo transfer of genes encoding beta-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) beta-synuclein (lenti-beta-synuclein) was tested in a transgenic (tg) mouse model of halpha-synuclein aggregation. This study showed that unilateral intracerebral injection of lenti-beta-synuclein reduced the formation of halpha-synuclein inclusions and the accumulation of halpha-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 beta-synuclein neuroprotection involve binding of this molecule to halpha-synuclein and Akt, resulting in the decreased aggregation and accumulation of halpha-synuclein in the synaptic membrane. Together, these data further support a role for beta-synuclein in regulating the conformational state of alpha-synuclein and suggest that this gene transfer approach might have potential for the development of alternative therapies for PD and DLB.
Insights
Gene therapy using beta-synuclein shows promise for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). This approach reduced alpha-synuclein accumulation and neurodegeneration in a mouse model, suggesting a novel treatment strategy.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are linked to alpha-synuclein accumulation.
- Current gene therapies for PD and DLB focus on different targets.
- Beta-synuclein, a nonamyloidogenic homologue, is a potential therapeutic candidate.
Purpose of the Study:
- To investigate the potential of beta-synuclein gene transfer as a novel therapeutic strategy for PD and DLB.
- To assess the efficacy of lentiviral beta-synuclein in a mouse model of alpha-synuclein aggregation.
- To elucidate the mechanisms underlying beta-synuclein's neuroprotective effects.
Main Methods:
- Development of a lentiviral vector expressing human beta-synuclein (lenti-beta-synuclein).
- Unilateral intracerebral injection of lenti-beta-synuclein into a transgenic mouse model of human alpha-synuclein aggregation.
- In vivo and in vitro coimmunoprecipitation and immunoblot experiments to analyze molecular interactions.
Main Results:
- Lenti-beta-synuclein injection reduced alpha-synuclein inclusions and synaptic accumulation in transgenic mice.
- Neurodegenerative alterations were ameliorated in the treated mice.
- Beta-synuclein was found to bind to alpha-synuclein and Akt, decreasing alpha-synuclein aggregation.
Conclusions:
- Beta-synuclein gene transfer effectively reduced alpha-synuclein pathology and neurodegeneration in a relevant mouse model.
- The neuroprotective mechanism involves beta-synuclein binding to alpha-synuclein and Akt, modulating aggregation.
- This gene therapy approach holds potential for developing novel treatments for PD and DLB.
