RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways

Marcel P. Van Der Brug, Jeff Blackinton, Jayanth Chandran, Ling Yang Hao, Ashish Lal, Krystyna Mazan-Mamczarz, Jennifer Martindale, Chengsong Xie, Rili Ahmad, Kelly J. Thomas, Alexandra Beilina, J. Raphael Gibbs, Jinhui Ding, Amanda J. Myers, Ming Zhan, Huaibin Cai, Nancy M. Bonini, Myriam Gorospe, Mark R. Cookson

Research output: Contribution to journalArticle

Abstract

Parkinson's disease (PD) is a major neurodegenerative condition with several rare Mendelian forms. Oxidative stress and mitochondrial function have been implicated in the pathogenesis of PD but the molecular mechanisms involved in the degeneration of neurons remain unclear. DJ-1 mutations are one cause of recessive parkinsonism, but this gene is also reported to be involved in cancer by promoting Ras signaling and suppressing PTEN-induced apoptosis. The specific function of DJ-1 is unknown, although it is responsive to oxidative stress and may play a role in the maintenance of mitochondria. Here, we show, using four independent methods, that DJ-1 associates with RNA targets in cells and the brain, including mitochondrial genes, genes involved in glutathione metabolism, and members of the PTEN/PI3K cascade. Pathogenic recessive mutants are deficient in this activity. We show that DJ-1 is sufficient for RNA binding at nanomolar concentrations. Further, we show that DJ-1 binds RNA but dissociates after oxidative stress. These data implicate a single mechanism for the pleiotropic effects of DJ-1 in different model systems, namely that the protein binds multiple RNA targets in an oxidation-dependent manner.

Original languageEnglish (US)
Pages (from-to)10244-10249
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number29
DOIs
StatePublished - Jul 22 2008
Externally publishedYes

Fingerprint

Parkinsonian Disorders
RNA
Oxidative Stress
Parkinson Disease
Recessive Genes
Nerve Degeneration
Mitochondrial Genes
Phosphatidylinositol 3-Kinases
Glutathione
Mitochondria
Maintenance
Apoptosis
Mutation
Protein Deglycase DJ-1
Brain
Genes
Neoplasms
Proteins

Keywords

  • Gene expression
  • Oxidative stress
  • Parkinson's disease
  • Translation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways. / Van Der Brug, Marcel P.; Blackinton, Jeff; Chandran, Jayanth; Hao, Ling Yang; Lal, Ashish; Mazan-Mamczarz, Krystyna; Martindale, Jennifer; Xie, Chengsong; Ahmad, Rili; Thomas, Kelly J.; Beilina, Alexandra; Gibbs, J. Raphael; Ding, Jinhui; Myers, Amanda J.; Zhan, Ming; Cai, Huaibin; Bonini, Nancy M.; Gorospe, Myriam; Cookson, Mark R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 29, 22.07.2008, p. 10244-10249.

Research output: Contribution to journalArticle

Van Der Brug, MP, Blackinton, J, Chandran, J, Hao, LY, Lal, A, Mazan-Mamczarz, K, Martindale, J, Xie, C, Ahmad, R, Thomas, KJ, Beilina, A, Gibbs, JR, Ding, J, Myers, AJ, Zhan, M, Cai, H, Bonini, NM, Gorospe, M & Cookson, MR 2008, 'RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 29, pp. 10244-10249. https://doi.org/10.1073/pnas.0708518105
Van Der Brug, Marcel P. ; Blackinton, Jeff ; Chandran, Jayanth ; Hao, Ling Yang ; Lal, Ashish ; Mazan-Mamczarz, Krystyna ; Martindale, Jennifer ; Xie, Chengsong ; Ahmad, Rili ; Thomas, Kelly J. ; Beilina, Alexandra ; Gibbs, J. Raphael ; Ding, Jinhui ; Myers, Amanda J. ; Zhan, Ming ; Cai, Huaibin ; Bonini, Nancy M. ; Gorospe, Myriam ; Cookson, Mark R. / RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 29. pp. 10244-10249.
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abstract = "Parkinson's disease (PD) is a major neurodegenerative condition with several rare Mendelian forms. Oxidative stress and mitochondrial function have been implicated in the pathogenesis of PD but the molecular mechanisms involved in the degeneration of neurons remain unclear. DJ-1 mutations are one cause of recessive parkinsonism, but this gene is also reported to be involved in cancer by promoting Ras signaling and suppressing PTEN-induced apoptosis. The specific function of DJ-1 is unknown, although it is responsive to oxidative stress and may play a role in the maintenance of mitochondria. Here, we show, using four independent methods, that DJ-1 associates with RNA targets in cells and the brain, including mitochondrial genes, genes involved in glutathione metabolism, and members of the PTEN/PI3K cascade. Pathogenic recessive mutants are deficient in this activity. We show that DJ-1 is sufficient for RNA binding at nanomolar concentrations. Further, we show that DJ-1 binds RNA but dissociates after oxidative stress. These data implicate a single mechanism for the pleiotropic effects of DJ-1 in different model systems, namely that the protein binds multiple RNA targets in an oxidation-dependent manner.",
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AU - Martindale, Jennifer

AU - Xie, Chengsong

AU - Ahmad, Rili

AU - Thomas, Kelly J.

AU - Beilina, Alexandra

AU - Gibbs, J. Raphael

AU - Ding, Jinhui

AU - Myers, Amanda J.

AU - Zhan, Ming

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AU - Gorospe, Myriam

AU - Cookson, Mark R.

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N2 - Parkinson's disease (PD) is a major neurodegenerative condition with several rare Mendelian forms. Oxidative stress and mitochondrial function have been implicated in the pathogenesis of PD but the molecular mechanisms involved in the degeneration of neurons remain unclear. DJ-1 mutations are one cause of recessive parkinsonism, but this gene is also reported to be involved in cancer by promoting Ras signaling and suppressing PTEN-induced apoptosis. The specific function of DJ-1 is unknown, although it is responsive to oxidative stress and may play a role in the maintenance of mitochondria. Here, we show, using four independent methods, that DJ-1 associates with RNA targets in cells and the brain, including mitochondrial genes, genes involved in glutathione metabolism, and members of the PTEN/PI3K cascade. Pathogenic recessive mutants are deficient in this activity. We show that DJ-1 is sufficient for RNA binding at nanomolar concentrations. Further, we show that DJ-1 binds RNA but dissociates after oxidative stress. These data implicate a single mechanism for the pleiotropic effects of DJ-1 in different model systems, namely that the protein binds multiple RNA targets in an oxidation-dependent manner.

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