α-synuclein expression from a single copy transgene increases sensitivity to stress and accelerates neuronal loss in genetic models of Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by the formation of alpha-synuclein-containing protein aggregates called Lewy bodies within the brain. A crucial role for alpha-synuclein in the pathogenesis of PD is also suggested by the fact that point mutations, increased copy number, or polymorphisms in the alpha-synuclein gene SNCA all cause or contribute to the development of PD. In addition to SNCA, an increasing number of other genes have been implicated in PD. While mutations in at least some of these genes have been shown to cause the formation of Lewy bodies, the role of alpha-synuclein in these genetic forms of PD remains poorly defined. Since C. elegans do not have a homolog of alpha-synuclein, this organism provides the opportunity to identify synergism between alpha-synuclein and other genes implicated in PD. To do this, we generated a novel C. elegans model in which wild-type alpha-synuclein is ubiquitously expressed from a single copy transgene, and examined the resulting effect on phenotypic deficits in PD deletion mutants affecting PARK2/pdr-1, PINK1/pink-1, DJ-1/djr-1.1 and ATP13A2/calp-6. While the PD deletion mutants exhibit only mild phenotypic deficits in absence of alpha-synuclein, expression of wild-type alpha-synuclein caused increased sensitivity to multiple stresses, induced deficits in dopamine-dependent behavior, and accelerated loss of dopamine neurons. Overall, these results suggest that the recessive loss of function mutations act together with alpha-synuclein to cause PD, and that alpha-synuclein lowering strategies may be effective in genetic forms of PD.