Overexpression of Parkinson's disease-associated alpha-synucleinA53T by recombinant adeno-associated virus in mice does not increase the vulnerability of dopaminergic neurons to MPTP.
Mutations in the alpha-synuclein gene are linked to a rare dominant form of familial Parkinson's disease, and alpha-synuclein is aggregated in Lewy bodies of both sporadic and dominant Parkinson's disease. It has been proposed that mutated alpha-synuclein causes dopaminergic neuron loss by enhancing the vulnerability of these neurons to a variety of insults, including oxidative stress, apoptotic stimuli, and selective dopaminergic neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To test this hypothesis in vivo, we overexpressed human alpha-synuclein(A53T) in the substantia nigra of normal and MPTP-treated mice by rAAV-mediated gene transfer. Determination of dopaminergic neuron survival, striatal tyrosine hydroxylase fiber density, and striatal content of dopamine and its metabolites in rAAV-injected and uninjected hemispheres demonstrated that alpha-synuclein(A53T) does not increase the susceptibility of dopaminergic neurons to MPTP. Our findings argue against a direct detrimental role for (mutant) alpha-synuclein in oxidative stress and/or apoptotic pathways triggered by MPTP, but do not rule out the possibility that alpha-synuclein aggregation in neurons exposed to oxidative stress for long periods of time may be neurotoxic.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D002452:Cell Count; D002470:Cell Survival; D004274:DNA, Recombinant; D000229:Dependovirus; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D018014:Gene Transfer Techniques; D006801:Humans; D007150:Immunohistochemistry; D020267:MPTP Poisoning / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010300:Parkinson Disease; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D051843:Synucleins; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein
D004274:DNA, Recombinant; D015259:Dopamine Agents; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine