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Research Article

DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway

Hossein Aleyasin, Maxime W. C. Rousseaux, Paul C. Marcogliese, Sarah J. Hewitt, Isabella Irrcher, Alvin P. Joselin, Mohammad Parsanejad, Raymond H. Kim, Patrizia Rizzu, Steve M. Callaghan, Ruth S. Slack, Tak W. Mak, and David S. Park
PNAS first published January 26, 2010; https://doi.org/10.1073/pnas.0914876107
Hossein Aleyasin
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Maxime W. C. Rousseaux
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Paul C. Marcogliese
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Sarah J. Hewitt
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Isabella Irrcher
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Alvin P. Joselin
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Mohammad Parsanejad
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Raymond H. Kim
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Patrizia Rizzu
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Steve M. Callaghan
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Ruth S. Slack
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Tak W. Mak
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  • For correspondence: dpark@uottawa.ca tmak@uhnresearch.ca
David S. Park
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  • For correspondence: dpark@uottawa.ca tmak@uhnresearch.ca
  1. Contributed by Tak Wah Mak, December 24, 2009 (sent for review December 15, 2009)

  2. ↵ 1H.A. and M.W.C.R. contributed equally to this work.

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Abstract

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 H2O2 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.

  • neurodegeneration
  • Parkinson disease
  • reactive oxygen species

Footnotes

  • 2To whom correspondence should be addressed. E-mail: dpark{at}uottawa.ca or tmak{at}uhnresearch.ca.
  • Author contributions: H.A., M.W.C.R., R.H.K., R.S.S., T.W.M., and D.S.P. designed research; H.A., M.W.C.R., P.C.M., S.J.H., I.I., A.P.J., and M.P. performed research; R.H.K., P.R., S.C., R.S.S., and T.W.M. contributed new reagents/analytic tools; H.A., M.W.C.R., P.C.M., S.J.H., A.P.J., M.P., and D.S.P. analyzed data; and H.A., M.W.C.R., I.I., and D.S.P. wrote the paper.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/cgi/content/full/0914876107/DCSupplemental.

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DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway
Hossein Aleyasin, Maxime W. C. Rousseaux, Paul C. Marcogliese, Sarah J. Hewitt, Isabella Irrcher, Alvin P. Joselin, Mohammad Parsanejad, Raymond H. Kim, Patrizia Rizzu, Steve M. Callaghan, Ruth S. Slack, Tak W. Mak, David S. Park
Proceedings of the National Academy of Sciences Jan 2010, 200914876; DOI: 10.1073/pnas.0914876107

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DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway
Hossein Aleyasin, Maxime W. C. Rousseaux, Paul C. Marcogliese, Sarah J. Hewitt, Isabella Irrcher, Alvin P. Joselin, Mohammad Parsanejad, Raymond H. Kim, Patrizia Rizzu, Steve M. Callaghan, Ruth S. Slack, Tak W. Mak, David S. Park
Proceedings of the National Academy of Sciences Jan 2010, 200914876; DOI: 10.1073/pnas.0914876107
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