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Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS

Seiji Watanabe1, Hristelina Ilieva2,3, Hiromi Tamada4

  • 1Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan.

EMBO Molecular Medicine
|November 9, 2016
PubMed

Insights

A novel mutation in the sigma 1 receptor (Sig1R) gene causes juvenile amyotrophic lateral sclerosis (ALS16). Loss of Sig1R function disrupts mitochondria-associated membranes (MAM), a common pathway in ALS.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Inherited juvenile amyotrophic lateral sclerosis (ALS16) is linked to mutations in the sigma 1 receptor (Sig1R) gene.
  • Sig1R is localized to the mitochondria-associated membrane (MAM), crucial for ER-mitochondria communication.
  • The precise role of MAM in ALS pathogenesis remains unclear.

Purpose of the Study:

  • Identify novel causes of ALS16.
  • Elucidate the role of Sig1R and MAM in ALS.
  • Investigate the link between Sig1R dysfunction, MAM integrity, and motor neuron vulnerability.

Main Methods:

  • Genetic analysis to identify Sig1R mutations.
  • Biochemical assays to assess Sig1R variant stability and IP3R3 binding.
  • In vivo studies using Sig1R-deficient mice and mutant SOD1 models.
  • Mitochondrial and cellular analyses to evaluate MAM integrity and function.

Main Results:

  • A homozygous p.L95fs mutation in Sig1R was identified as a novel cause of ALS16.
  • ALS-linked Sig1R variants exhibit instability and impaired IP3R3 binding.
  • Sig1R deficiency accelerates mutant SOD1-ALS onset in mice.
  • Both Sig1R deficiency and mutant SOD1 accumulation disrupt MAM, leading to IP3R3 mislocalization, calpain activation, and mitochondrial dysfunction.

Conclusions:

  • Loss of Sig1R function is causative for ALS16.
  • MAM collapse is a shared pathomechanism in Sig1R- and SOD1-linked ALS.
  • MAM integrity is critical for selective motor neuron vulnerability in ALS, highlighted by IP3R3 enrichment.
Keywords:
amyotrophic lateral sclerosisinositol 1,4,5‐triphosphate receptor type 3mitochondria‐associated membranesigma 1 receptor

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