Beta-synuclein modulates alpha-synuclein neurotoxicity by reducing alpha-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 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.
Fan
Yuxin
Y
Department of Laboratory Medicine, University of Washington Medical Center, Seattle, WA, USA.
Limprasert
Pornprot
P
Murray
Ian V J
IV
Smith
Annette C
AC
Lee
Virginia M-Y
VM
Trojanowski
John Q
JQ
Sopher
Bryce L
BL
La Spada
Albert R
AR
D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology; D011328:Prions / Q000235:genetics; D051844:alpha-Synuclein / Q000378:metabolism*; D051846:beta-Synuclein / Q000235:genetics / Q000378:metabolism*
D011328:Prions; D051844:alpha-Synuclein; D051846:beta-Synuclein