β-synuclein modulates α-synuclein neurotoxicity by reducing α-synuclein protein expression

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of α-synuclein in characteristic inclusions known as 'Lewy bodies'. As mutations altering α-synuclein structure or increasing α-synuclein expression level can cause familial forms of PD or related Lewy body disorders, α-synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in 'synucleinopathies'. p-synuclein is closely related to α-synuclein and has been shown to inhibit α-synuclein aggregation and ameliorate α-synuclein neurotoxicity. We generated p-synuclein transgenic mice and observed a marked reduction in α-synuclein protein expression in the cortex of mice over-expressing p-synuclein. This reduction in α-synuclein protein expression was not accompanied by decreases in α-synuclein mRNA expression. Using the prion protein promoter α-synuclein A53T mouse model of PD, we demonstrated that over-expression of p-synuclein could retard the progression of impaired motor performance, reduce α-synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of α-synuclein neurotoxicity in such bigenic mice to the ability of p-synuclein to reduce α-synuclein protein expression based upon I 125 autoradiography quantification. Our findings indicate that increased expression of p-synuclein protein results in a reduction of α-synuclein protein expression. As increased expression of α-synuclein may cause or contribute to PD pathogenesis in sporadic and familial forms of disease, this observation has important implications for the development of therapies for PD.