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.