Mutant SOD1 forms ion channel: Implications for ALS pathophysiology

Michael J. Allen; Jérome J. Lacroix; Srinivasan Ramachandran; Ricardo Capone; Jenny L. Whitlock; Ghanashyam D. Ghadge; Morton F. Arnsdorf; Raymond P. Roos; Ratnesh Lal

Neurobiology of Disease (Mar 2012)

Mutant SOD1 forms ion channel: Implications for ALS pathophysiology

Michael J. Allen,
Jérome J. Lacroix,
Srinivasan Ramachandran,
Ricardo Capone,
Jenny L. Whitlock,
Ghanashyam D. Ghadge,
Morton F. Arnsdorf,
Raymond P. Roos,
Ratnesh Lal

Affiliations

Michael J. Allen: Center for Nanomedicine and Section of Pulmonary/Critical Care, Department of Medicine, The University of Chicago, Chicago, IL, USA
Jérome J. Lacroix: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA
Srinivasan Ramachandran: Department of Bioengineering, Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA
Ricardo Capone: Department of Bioengineering, Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA
Jenny L. Whitlock: Center for Nanomedicine and Section of Pulmonary/Critical Care, Department of Medicine, The University of Chicago, Chicago, IL, USA
Ghanashyam D. Ghadge: Department of Neurology, The University of Chicago, Chicago, IL, USA
Morton F. Arnsdorf: Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, IL, USA
Raymond P. Roos: Department of Neurology, The University of Chicago, Chicago, IL, USA; Correspondence to: R.P. Roos, Department of Neurology, The University of Chicago, 5841 S. Maryland Avenue, MC 2030, Chicago, IL, USA. Fax: +1 773 834 9089.
Ratnesh Lal: Department of Bioengineering, Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA; Correspondence to: R. Lal, Department of Bioengineering and Mechanical & Aerospace engineering, 9500 Gilman Dr., PFBH-217, University of California San Diego, La Jolla, CA 92093–0412, USA. Fax: +1 858 822 5846.

Journal volume & issue: Vol. 45, no. 3
pp. 831 – 838

Abstract

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Point mutations in the gene encoding copper–zinc superoxide dismutase (SOD1) impart a gain-of-function to this protein that underlies 20–25% of all familial amyotrophic lateral sclerosis (FALS) cases. However, the specific mechanism of mutant SOD1 toxicity has remained elusive. Using the complementary techniques of atomic force microscopy (AFM), electrophysiology, and cell and molecular biology, here we examine the structure and activity of A4VSOD1, a mutant SOD1. AFM of A4VSOD1 reconstituted in lipid membrane shows discrete tetrameric pore-like structure with outer and inner diameters 12.2 and 3.0 nm respectively. Electrophysiological recordings show distinct ionic conductances across bilayer for A4VSOD1 and none for wildtype SOD1. Mouse neuroblastoma cells exposed to A4VSOD1 undergo membrane depolarization and increases in intracellular calcium. These results provide compelling new evidence that a mutant SOD1 is capable of disrupting cellular homeostasis via an unregulated ion channel mechanism. Such a “toxic channel” mechanism presents a new therapeutic direction for ALS research.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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