First Author | Thomas B | Year | 2011 |
Journal | PLoS One | Volume | 6 |
Issue | 1 | Pages | e16706 |
PubMed ID | 21304957 | Mgi Jnum | J:169549 |
Mgi Id | MGI:4941270 | Doi | 10.1371/journal.pone.0016706 |
Citation | Thomas B, et al. (2011) Resistance to MPTP-neurotoxicity in alpha-synuclein knockout mice is complemented by human alpha-synuclein and associated with increased beta-synuclein and Akt activation. PLoS One 6(1):e16706 |
abstractText | Genetic and biochemical abnormalities of alpha-synuclein are associated with the pathogenesis of Parkinson's disease. In the present study we investigated the in vivo interaction of mouse and human alpha-synuclein with the potent parkinsonian neurotoxin, MPTP. We find that while lack of mouse alpha-synuclein in mice is associated with reduced vulnerability to MPTP, increased levels of human alpha-synuclein expression is not associated with obvious changes in the vulnerability of dopaminergic neurons to MPTP. However, expressing human alpha-synuclein variants (human wild type or A53T) in the alpha-synuclein null mice completely restores the vulnerability of nigral dopaminergic neurons to MPTP. These results indicate that human alpha-synuclein can functionally replace mouse alpha-synuclein in regard to vulnerability of dopaminergic neurons to MPTP-toxicity. Significantly, alpha-synuclein null mice and wild type mice were equally sensitive to neurodegeneration induced by 2'NH(2)-MPTP, a MPTP analog that is selective for serotoninergic and noradrenergic neurons. These results suggest that effects of alpha-synuclein on MPTP like compounds are selective for nigral dopaminergic neurons. Immunoblot analysis of beta-synuclein and Akt levels in the mice reveals selective increases in beta-synuclein and phosphorylated Akt levels in ventral midbrain, but not in other brain regions, of alpha-synuclein null mice, implicating the alpha-synuclein-level dependent regulation of beta-synuclein expression in modulation of MPTP-toxicity by alpha-synuclein. Together these findings provide new mechanistic insights on the role alpha-synuclein in modulating neurodegenerative phenotypes by regulation of Akt-mediated cell survival signaling in vivo. |