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CIIA prevents SOD1(G93A)-induced cytotoxicity by blocking ASK1-mediated signaling

Jae Keun Lee1, Sang Gil Hwang1, Jin Hee Shin2

  • 1Laboratory of Cell Death and Human Diseases, Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University Seoul, South Korea.

Frontiers in Cellular Neuroscience
|July 15, 2014
PubMed

Insights

Depleting CIIA expression worsened toxicity in a cellular model of amyotrophic lateral sclerosis (ALS). Silencing CIIA enhanced SOD1(G93A)-induced cell death signaling, suggesting CIIA is protective in ALS.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease impacting motor neurons.
  • The precise molecular mechanisms driving neurotoxicity in ALS, particularly from SOD1 mutations, are not fully understood.

Purpose of the Study:

  • To investigate the role of CIIA in the neurotoxicity induced by the G93A mutant of human superoxide dismutase 1 (SOD1) in a cellular model of ALS.
  • To elucidate the molecular pathways modulated by CIIA in SOD1(G93A)-induced cytotoxicity.

Main Methods:

  • RNA interference (RNAi) was used to deplete CIIA expression in cells expressing the SOD1(G93A) mutant.
  • Assays were performed to measure cytotoxicity, ASK1-TRAF2 interaction and activity, mitochondrial membrane potential, cytochrome c release, and caspase activation.

Main Results:

  • Depletion of CIIA expression exacerbated SOD1(G93A)-induced cytotoxicity.
  • Knockdown of CIIA enhanced the interaction between ASK1 and TRAF2 and increased ASK1 activity.
  • Silencing CIIA potentiated SOD1(G93A)-mediated reduction in mitochondrial membrane potential, cytochrome c release, and caspase activation.

Conclusions:

  • CIIA acts as a negative modulator of ASK1-mediated cytotoxic signaling pathways in a cellular model of ALS expressing SOD1(G93A).
  • These findings suggest a potential protective role for CIIA in ALS pathogenesis.
Keywords:
ALS (amyotrophic lateral sclerosis)ASK1 (apoptosis signal-regulating kinase 1)ROS (reactive oxygen species)cytotoxicitymitochondria

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