DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway.
Loss-of-function DJ-1 (PARK7) mutations have been linked with a familial form of early onset Parkinson disease. Numerous studies have supported the role of DJ-1 in neuronal survival and function. Our initial studies using DJ-1-deficient neurons indicated that DJ-1 specifically protects the neurons against the damage induced by oxidative injury in multiple neuronal types and degenerative experimental paradigms, both in vitro and in vivo. However, the manner by which oxidative stress-induced death is ameliorated by DJ-1 is not completely clear. We now present data that show the involvement of DJ-1 in modulation of AKT, a major neuronal prosurvival pathway induced upon oxidative stress. We provide evidence that DJ-1 promotes AKT phosphorylation in response to oxidative stress induced by H(2)O(2) in vitro and in vivo following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Moreover, we show that DJ-1 is necessary for normal AKT-mediated protective effects, which can be bypassed by expression of a constitutively active form of AKT. Taken together, these data suggest that DJ-1 is crucial for full activation of AKT upon oxidative injury, which serves as one explanation for the protective effects of DJ-1.
Aleyasin
Hossein
H
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Rousseaux
Maxime W C
MW
Marcogliese
Paul C
PC
Hewitt
Sarah J
SJ
Irrcher
Isabella
I
Joselin
Alvin P
AP
Parsanejad
Mohammad
M
Kim
Raymond H
RH
Rizzu
Patrizia
P
Callaghan
Steve M
SM
Slack
Ruth S
RS
Mak
Tak W
TW
Park
David S
DS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002458:Cell Fractionation; D002478:Cells, Cultured; D006861:Hydrogen Peroxide / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D054464:Peroxiredoxins; D010766:Phosphorylation; D000071617:Protein Deglycase DJ-1; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D009498:Neurotoxins; D015513:Oncogene Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D051057:Proto-Oncogene Proteins c-akt; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1