Mice lacking alpha-synuclein are resistant to mitochondrial toxins.
Abnormalities in the function of alpha-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). We found that alpha-synuclein-deficient mice are resistant to MPTP-induced degeneration of dopaminergic neurons. There was dose-dependent protection against loss of both dopamine in the striatum and dopamine transporter (DAT) immunoreactive neurons in the substantia nigra. These effects were not due to alterations in MPTP processing. We found that alpha-synuclein-deficient mice are also resistant to both malonate and 3-nitropropionic acid (3-NP) neurotoxicity. There was reduced generation of reactive oxygen species in alpha-synuclein-deficient mice following administration of 3-NP. These findings implicate alpha-synuclein as a modulator of oxidative damage, which has been implicated in neuronal death produced by MPTP and other mitochondrial toxins.
Klivenyi
Peter
P
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, 525 East 68th Street, New York, NY 10021, USA.
Siwek
Donald
D
Gardian
Gabrielle
G
Yang
Lichuan
L
Starkov
Anatoly
A
Cleren
Carine
C
Ferrante
Robert J
RJ
Kowall
Neil W
NW
Abeliovich
Asa
A
Beal
M Flint
MF
D000818:Animals; D008314:Malonates / Q000633:toxicity; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology*; D009574:Nitro Compounds / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology*; D011422:Propionates / Q000633:toxicity; D051844:alpha-Synuclein / Q000172:deficiency* / Q000235:genetics
D008314:Malonates; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D051844:alpha-Synuclein; C030290:malonic acid; C015392:3-nitropropionic acid