부산대학교 도서관

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 fora-synuclein accumulation in the pathogenesis of these disorders, an alternative therapy might require the transfer of genes that might blocka-synuclein accumulation.ß-Synuclein, the nonamyloidogenic homologue ofa-synuclein, has recently been identified as a potential candidate. Thus, in vivo transfer of genes encodingß-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)ß-synuclein (lenti-ß-synuclein) was tested in a transgenic (tg) mouse model of ha-synuclein aggregation. This study showed that unilateral intracerebral injection of lenti-ß-synuclein reduced the formation of ha-synuclein inclusions and the accumulation of ha-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 ofß-synuclein neuroprotection involve binding of this molecule to ha-synuclein and Akt, resulting in the decreased aggregation and accumulation of ha-synuclein in the synaptic membrane. Together, these data further support a role forß-synuclein in regulating the conformational state ofa-synuclein and suggest that this gene transfer approach might have potential for the development of alternative therapies for PD and DLB.Gene Therapy (2004) 11, 1713-1723. doi:10.1038/sj.gt.3302349; Published online 14 October 2004 [ABSTRACT FROM AUTHOR]