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- Title
β-synuclein modulates α-synuclein neurotoxicity by reducing α-synuclein protein expression.
- Authors
Fan, Yuxin; Limprasert, Pornprot; Murray, Ian V.J.; Smith, Annette C.; Lee, Virginia M.-Y.; Trojanowski, John Q.; Sopher, Bryce L.; La Spada, Albert R.
- Abstract
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.
- Publication
Human Molecular Genetics, 2006, Vol 15, Issue 20, p3002
- ISSN
0964-6906
- Publication type
Academic Journal
- DOI
10.1093/hmg/ddl242