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′NH2-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.
Highlights
Parkinson’s disease (PD) is predominantly an idiopathic disorder without cure and with limited symptomatic treatment
We find that the levels of b-synuclein and phosphorylated Akt is inversely correlated with a-synuclein expression in the nigro-striatal system and increased b-synuclein and phosphorylated Akt levels correlate with the protection from MPTP toxicity
MPTP treatment results in increased striatal dopamine turnover (DOPAC/DA) which is not statistically different in any of the transgenic lines compared to non-transgenic animals
Summary
Parkinson’s disease (PD) is predominantly an idiopathic disorder without cure and with limited symptomatic treatment. PD is marked by a selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) characterized by movement abnormalities including resting tremor, bradykinesia, postural instabiltity and rigidity[1]. Both environmental and genetic factors are implicated in the pathogenesis of PD [2]. The genetic cause for PD was first established with identification of mutations in the gene encoding for the synaptic protein a-synuclein in several families with the autosomal dominant form of PD [3,4,5,6]. The PLoS ONE | www.plosone.org a-Synuclein Dependent Regulation of b-Synuclein mechanistic basis for a-synuclein abnormalities and dopaminergic degeneration is unresolved
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