%0 Journal Article
%T Resistance to MPTP-Neurotoxicity in ¦Á-Synuclein Knockout Mice Is Complemented by Human ¦Á-Synuclein and Associated with Increased ¦Â-Synuclein and Akt Activation
%A Bobby Thomas
%A Allen S. Mandir
%A Neva West
%A Ying Liu
%A Shaida A. Andrabi
%A Wanda Stirling
%A Valina L. Dawson
%A Ted M. Dawson
%A Michael K. Lee
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0016706
%X Genetic and biochemical abnormalities of ¦Á-synuclein are associated with the pathogenesis of Parkinson's disease. In the present study we investigated the in vivo interaction of mouse and human ¦Á-synuclein with the potent parkinsonian neurotoxin, MPTP. We find that while lack of mouse ¦Á-synuclein in mice is associated with reduced vulnerability to MPTP, increased levels of human ¦Á-synuclein expression is not associated with obvious changes in the vulnerability of dopaminergic neurons to MPTP. However, expressing human ¦Á-synuclein variants (human wild type or A53T) in the ¦Á-synuclein null mice completely restores the vulnerability of nigral dopaminergic neurons to MPTP. These results indicate that human ¦Á-synuclein can functionally replace mouse ¦Á-synuclein in regard to vulnerability of dopaminergic neurons to MPTP-toxicity. Significantly, ¦Á-synuclein null mice and wild type mice were equally sensitive to neurodegeneration induced by 2¡äNH2-MPTP, a MPTP analog that is selective for serotoninergic and noradrenergic neurons. These results suggest that effects of ¦Á-synuclein on MPTP like compounds are selective for nigral dopaminergic neurons. Immunoblot analysis of ¦Â-synuclein and Akt levels in the mice reveals selective increases in ¦Â-synuclein and phosphorylated Akt levels in ventral midbrain, but not in other brain regions, of ¦Á-synuclein null mice, implicating the ¦Á-synuclein-level dependent regulation of ¦Â-synuclein expression in modulation of MPTP-toxicity by ¦Á-synuclein. Together these findings provide new mechanistic insights on the role ¦Á-synuclein in modulating neurodegenerative phenotypes by regulation of Akt-mediated cell survival signaling in vivo.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016706