1. ¹Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
2. ²Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA
3. ³Department of Pathology, University of California San Diego, La Jolla, CA, USA

Correspondence: Dr E Masliah, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, USA

Received 1 December 2003; Accepted 16 June 2004; Published online 14 October 2004.

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 -synuclein accumulation in the pathogenesis of these disorders, an alternative therapy might require the transfer of genes that might block -synuclein accumulation. -Synuclein, the nonamyloidogenic homologue of -synuclein, has recently been identified as a potential candidate. Thus, in vivo transfer of genes encoding -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) -synuclein (lenti--synuclein) was tested in a transgenic (tg) mouse model of h-synuclein aggregation. This study showed that unilateral intracerebral injection of lenti--synuclein reduced the formation of h-synuclein inclusions and the accumulation of h-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 -synuclein neuroprotection involve binding of this molecule to h-synuclein and Akt, resulting in the decreased aggregation and accumulation of h-synuclein in the synaptic membrane. Together, these data further support a role for -synuclein in regulating the conformational state of -synuclein and suggest that this gene transfer approach might have potential for the development of alternative therapies for PD and DLB.