b-synuclein modulates a-synuclein neurotoxicity by reducing a-synuclein protein expression

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