Journal Article

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

Yuxin Fan, Pornprot Limprasert, Ian V.J. Murray, Annette C. Smith, Virginia M.-Y. Lee, John Q. Trojanowski, Bryce L. Sopher and Albert R. La Spada

in Human Molecular Genetics

Volume 15, issue 20, pages 3002-3011
Published in print October 2006 | ISSN: 0964-6906
Published online September 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl242
β-synuclein modulates α-synuclein neurotoxicity by reducing α-synuclein protein expression

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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’. β-synuclein is closely related to α-synuclein and has been shown to inhibit α-synuclein aggregation and ameliorate α-synuclein neurotoxicity. We generated β-synuclein transgenic mice and observed a marked reduction in α-synuclein protein expression in the cortex of mice over-expressing β-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 β-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 β-synuclein to reduce α-synuclein protein expression based upon I125 autoradiography quantification. Our findings indicate that increased expression of β-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.

Journal Article.  5100 words.  Illustrated.

Subjects: Genetics and Genomics

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