title: Resistance to MPTP-neurotoxicity in α-synuclein knockout mice is complemented by human α-synuclein and associated with increased β-synuclein and Akt activation.
abstract: Genetic and biochemical abnormalities of α-synuclein are associated with the pathogenesis of Parkinson's disease. In the present study we investigated the in vivo interaction of mouse and human α-synuclein with the potent parkinsonian neurotoxin, MPTP. We find that while lack of mouse α-synuclein in mice is associated with reduced vulnerability to MPTP, increased levels of human α-synuclein expression is not associated with obvious changes in the vulnerability of dopaminergic neurons to MPTP. However, expressing human α-synuclein variants (human wild type or A53T) in the α-synuclein null mice completely restores the vulnerability of nigral dopaminergic neurons to MPTP. These results indicate that human α-synuclein can functionally replace mouse α-synuclein in regard to vulnerability of dopaminergic neurons to MPTP-toxicity. Significantly, α-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 α-synuclein on MPTP like compounds are selective for nigral dopaminergic neurons. Immunoblot analysis of β-synuclein and Akt levels in the mice reveals selective increases in β-synuclein and phosphorylated Akt levels in ventral midbrain, but not in other brain regions, of α-synuclein null mice, implicating the α-synuclein-level dependent regulation of β-synuclein expression in modulation of MPTP-toxicity by α-synuclein. Together these findings provide new mechanistic insights on the role α-synuclein in modulating neurodegenerative phenotypes by regulation of Akt-mediated cell survival signaling in vivo.
authors.affiliation: Neuroregeneration and Stem Cell Programs, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Bobby
authors.initials: B
authors.lastname: Thomas
authors.forename: Allen S
authors.initials: AS
authors.lastname: Mandir
authors.forename: Neva
authors.initials: N
authors.lastname: West
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Shaida A
authors.initials: SA
authors.lastname: Andrabi
authors.forename: Wanda
authors.initials: W
authors.lastname: Stirling
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Michael K
authors.initials: MK
authors.lastname: Lee
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival; D015259:Dopamine Agents / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D020267:MPTP Poisoning / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control*; D009498:Neurotoxins / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D051844:alpha-Synuclein / Q000172:deficiency*; D051846:beta-Synuclein / Q000502:physiology*
chemical_list: D015259:Dopamine Agents; D009498:Neurotoxins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051058:Oncogene Protein v-akt