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Familial amyotrophic lateral sclerosis-linked mutant SOD1 aberrantly interacts with tubulin

Tomohiro Kabuta1, Aiko Kinugawa, Yukihiro Tsuchiya

  • 1Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. kabuta@ncnp.go.jp

Biochemical and Biophysical Research Communications
|July 7, 2009
PubMed

Insights

Mutant copper-zinc superoxide dismutase (SOD1) interacts with alpha/beta-tubulin, a key protein for neuronal health. This interaction disrupts tubulin function, potentially driving motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS).

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Familial amyotrophic lateral sclerosis (ALS) is linked to mutations in the copper-zinc superoxide dismutase (SOD1) gene.
  • Mutant SOD1 induces motor neuron death via toxic gain-of-function mechanisms.
  • The precise molecular targets of mutant SOD1 remain incompletely understood.

Purpose of the Study:

  • To identify direct molecular targets of mutant SOD1 responsible for its toxicity.
  • To investigate the interaction between mutant SOD1 and alpha/beta-tubulin.

Main Methods:

  • Utilized G93A SOD1 transgenic mouse model.
  • Detected protein-protein interactions in spinal cord tissue.
  • Performed cell-free tubulin polymerization assays.
  • Analyzed protein solubility.

Main Results:

  • Alpha/beta-tubulin was identified as a major interacting protein with mutant SOD1, but not wild-type SOD1.
  • Interaction occurred in the spinal cords of pre-symptomatic G93A SOD1 mice.
  • Mutant SOD1 binding sites on tubulin were mapped to residues 1-23 and 116-153.
  • Mutant SOD1 overexpression led to tubulin accumulation in insoluble cellular fractions.
  • Mutant SOD1, but not wild-type SOD1, modulated tubulin polymerization in vitro.

Conclusions:

  • Alpha/beta-tubulin is a direct molecular target of mutant SOD1.
  • Disruption of microtubule dynamics by mutant SOD1 may contribute to motor neuron degeneration in ALS.
  • Targeting the mutant SOD1-tubulin interaction could offer a therapeutic strategy for ALS.

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