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 alpha-synuclein in characteristic inclusions known as "Lewy bodies". As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial form...

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Bibliographic Details
Published in:Human molecular genetics 2006-10, Vol.15 (20), p.3002-3011
Main Authors: YUXIN FAN, LIMPRASERT, Pornprot, MURRAY, Ian V. J, SMITH, Annette C, LEE, Virginia M.-Y, TROJANOWSKI, John Q, SOPHER, Bryce L, LA SPADA, Albert R
Format: Article
Language:English
Subjects:
alpha-Synuclein - metabolism
Animals
beta-Synuclein - genetics
beta-Synuclein - metabolism
Biological and medical sciences
Fundamental and applied biological sciences. Psychology
Genetics of eukaryotes. Biological and molecular evolution
Humans
Mice
Mice, Transgenic
Molecular and cellular biology
Parkinson Disease - metabolism
Parkinson Disease - physiopathology
Parkinson Disease - psychology
Prions - genetics
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Summary:Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of alpha-synuclein in characteristic inclusions known as "Lewy bodies". As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial forms of PD or related Lewy body disorders, alpha-synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in "synucleinopathies". beta-synuclein is closely related to alpha-synuclein and has been shown to inhibit alpha-synuclein aggregation and ameliorate alpha-synuclein neurotoxicity. We generated beta-synuclein transgenic mice and observed a marked reduction in alpha-synuclein protein expression in the cortex of mice over-expressing beta-synuclein. This reduction in alpha-synuclein protein expression was not accompanied by decreases in alpha-synuclein mRNA expression. Using the prion protein promoter alpha-synuclein A53T mouse model of PD, we demonstrated that over-expression of beta-synuclein could retard the progression of impaired motor performance, reduce alpha-synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of alpha-synuclein neurotoxicity in such bigenic mice to the ability of beta-synuclein to reduce alpha-synuclein protein expression based upon I(125) autoradiography quantification. Our findings indicate that increased expression of beta-synuclein protein results in a reduction of alpha-synuclein protein expression. As increased expression of alpha-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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddl242