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Isocitrate protects DJ-1 null dopaminergic cells from oxidative stress through NADP+-dependent isocitrate dehydrogenase (IDH)

Title
Isocitrate protects DJ-1 null dopaminergic cells from oxidative stress through NADP+-dependent isocitrate dehydrogenase (IDH)
Authors
Yang J.Kim M.J.Yoon W.Kim E.Y.Kim H.Lee Y.Min B.Kang K.S.Son J.H.Park H.T.Chung J.Koh H.
Ewha Authors
손형진
SCOPUS Author ID
손형진scopus
Issue Date
2017
Journal Title
PLoS Genetics
ISSN
1553-7390JCR Link
Citation
vol. 13, no. 8
Publisher
Public Library of Science
Indexed
SCOPUS WOS scopus
Abstract
DJ-1 is one of the causative genes for early onset familiar Parkinson’s disease (PD) and is also considered to influence the pathogenesis of sporadic PD. DJ-1 has various physiological functions which converge on controlling intracellular reactive oxygen species (ROS) levels. In RNA-sequencing analyses searching for novel anti-oxidant genes downstream of DJ-1, a gene encoding NADP+-dependent isocitrate dehydrogenase (IDH), which converts isocitrate into α-ketoglutarate, was detected. Loss of IDH induced hyper-sensitivity to oxidative stress accompanying age-dependent mitochondrial defects and dopaminergic (DA) neuron degeneration in Drosophila, indicating its critical roles in maintaining mitochondrial integrity and DA neuron survival. Further genetic analysis suggested that DJ-1 controls IDH gene expression through nuclear factor-E2-related factor2 (Nrf2). Using Drosophila and mammalian DA models, we found that IDH suppresses intracellular and mitochondrial ROS level and subsequent DA neuron loss downstream of DJ-1. Consistently, trimethyl isocitrate (TIC), a cell permeable isocitrate, protected mammalian DJ-1 null DA cells from oxidative stress in an IDH-dependent manner. These results suggest that isocitrate and its derivatives are novel treatments for PD associated with DJ-1 dysfunction. © 2017 Yang et al.
DOI
10.1371/journal.pgen.1006975
Appears in Collections:
약학대학 > 약학과 > Journal papers
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