Human Molecular Genetics Advance Access originally published online on September 7, 2006
Human Molecular Genetics 2006 15(20):3002-3011; doi:10.1093/hmg/ddl242
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ß-synuclein modulates 
-synuclein neurotoxicity by reducing -synuclein protein expression
1 Department of Laboratory Medicine, 2 Department of Medicine, 3 Department of Neurology and 4 The Center for Neurogenetics and Neurotherapeutics, University of Washington Medical Center, Seattle, WA, USA and 5 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine and 6 Institute on Aging, University of Pennsylvania, Philadelphia, PA, USA
* To whom correspondence should be addressed at: Department of Laboratory Medicine, University of Washington Medical Center, Box 357110, Room NW 120, Seattle, WA, USA. Tel: +1 2065982138; Fax: +1 2065986189; Email: laspada{at}u.washington.edu
Received August 7, 2006; Revised August 25, 2006; Accepted September 4, 2006
Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of 
-synuclein in characteristic inclusions known as ‘Lewy bodies’. As mutations altering -synuclein structure or increasing -synuclein expression level can cause familial forms of PD or related Lewy body disorders, -synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in ‘synucleinopathies’. ß-synuclein is closely related to -synuclein and has been shown to inhibit -synuclein aggregation and ameliorate -synuclein neurotoxicity. We generated ß-synuclein transgenic mice and observed a marked reduction in -synuclein protein expression in the cortex of mice over-expressing ß-synuclein. This reduction in -synuclein protein expression was not accompanied by decreases in -synuclein mRNA expression. Using the prion protein promoter -synuclein A53T mouse model of PD, we demonstrated that over-expression of ß-synuclein could retard the progression of impaired motor performance, reduce -synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of -synuclein neurotoxicity in such bigenic mice to the ability of ß-synuclein to reduce -synuclein protein expression based upon I125 autoradiography quantification. Our findings indicate that increased expression of ß-synuclein protein results in a reduction of -synuclein protein expression. As increased expression of -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.
Present address: Department of Pathology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand.
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