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Mutant SOD1 forms ion channel: implications for ALS pathophysiology

Michael J Allen1, Jérome J Lacroix, Srinivasan Ramachandran

  • 1Center for Nanomedicine and Section of Pulmonary/Critical Care, Department of Medicine, The University of Chicago, Chicago, IL, USA.

Neurobiology of Disease
|September 21, 2011
PubMed

Insights

Mutant copper-zinc superoxide dismutase (SOD1) forms toxic ion channels, disrupting cell function in familial amyotrophic lateral sclerosis (FALS). This discovery offers new therapeutic targets for FALS research.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Point mutations in copper-zinc superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS).
  • The exact mechanism of mutant SOD1 toxicity is not fully understood.

Purpose of the Study:

  • To investigate the structure and function of a specific mutant SOD1 (A4VSOD1).
  • To elucidate the toxic mechanism underlying mutant SOD1 in FALS.

Main Methods:

  • Atomic force microscopy (AFM) to visualize A4VSOD1 structure.
  • Electrophysiology to assess ion channel activity.
  • Cellular and molecular biology techniques to study cellular effects.

Main Results:

  • AFM revealed a tetrameric pore-like structure of A4VSOD1 in lipid membranes.
  • Electrophysiology demonstrated distinct ionic conductances for A4VSOD1, unlike wildtype SOD1.
  • A4VSOD1 induced membrane depolarization and calcium influx in neuroblastoma cells.

Conclusions:

  • Mutant SOD1 can form an unregulated ion channel, disrupting cellular homeostasis.
  • This "toxic channel" mechanism provides a novel therapeutic avenue for FALS research.

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