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

Jinsung Yang1, Min Ju Kim2, Woongchang Yoon1

  • 1National Creative Research Initiatives Center for Energy Homeostasis Regulation, School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Republic of Korea.

Plos Genetics
|August 23, 2017
PubMed

Insights

DJ-1 dysfunction contributes to Parkinson's disease (PD). This study identifies isocitrate dehydrogenase (IDH) as a key protective gene, suggesting isocitrate derivatives as potential PD treatments.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • DJ-1 is implicated in both familial and sporadic Parkinson's disease (PD).
  • DJ-1's function involves regulating intracellular reactive oxygen species (ROS) levels.
  • Oxidative stress and mitochondrial dysfunction are key factors in dopaminergic (DA) neuron degeneration in PD.

Purpose of the Study:

  • To identify novel antioxidant genes regulated by DJ-1.
  • To investigate the role of NADP+-dependent isocitrate dehydrogenase (IDH) in DJ-1-associated neuroprotection.
  • To explore isocitrate and its derivatives as potential therapeutic agents for PD.

Main Methods:

  • RNA-sequencing analysis to identify DJ-1 downstream genes.
  • Genetic manipulation in Drosophila models to assess IDH function in oxidative stress and DA neuron survival.
  • Utilized mammalian cell and animal models of DJ-1 deficiency and DA neurodegeneration.
  • Investigated the regulatory pathway involving DJ-1, Nrf2, and IDH gene expression.

Main Results:

  • Loss of IDH in Drosophila led to oxidative stress sensitivity, mitochondrial defects, and DA neuron degeneration.
  • DJ-1 was found to control IDH gene expression via the Nrf2 pathway.
  • IDH suppressed ROS levels and protected DA neurons in both Drosophila and mammalian models downstream of DJ-1.
  • Trimethyl isocitrate (TIC) protected DJ-1 deficient DA cells from oxidative stress in an IDH-dependent manner.

Conclusions:

  • IDH plays a critical role in maintaining mitochondrial integrity and DA neuron survival, acting downstream of DJ-1.
  • Isocitrate and its derivatives demonstrate therapeutic potential for Parkinson's disease linked to DJ-1 dysfunction.

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