RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways.
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.
van der Brug
Marcel P
MP
Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707, USA.
Blackinton
Jeff
J
Chandran
Jayanth
J
Hao
Ling-Yang
LY
Lal
Ashish
A
Mazan-Mamczarz
Krystyna
K
Martindale
Jennifer
J
Xie
Chengsong
C
Ahmad
Rili
R
Thomas
Kelly J
KJ
Beilina
Alexandra
A
Gibbs
J Raphael
JR
Ding
Jinhui
J
Myers
Amanda J
AJ
Zhan
Ming
M
Cai
Huaibin
H
Bonini
Nancy M
NM
Gorospe
Myriam
M
Cookson
Mark R
MR
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics; D050259:Genes, Mitochondrial; D005808:Genes, Recessive; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000071617:Protein Deglycase DJ-1; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D054464:Peroxiredoxins; D019869:Phosphatidylinositol 3-Kinases; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005978:Glutathione