title: Mutant SOD1 forms ion channel: implications for ALS pathophysiology.
abstract: 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 3.0nm 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.
authors.affiliation: Center for Nanomedicine and Section of Pulmonary/Critical Care, Department of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allen
authors.forename: Jérome J
authors.initials: JJ
authors.lastname: Lacroix
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Ricardo
authors.initials: R
authors.lastname: Capone
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Whitlock
authors.forename: Ghanashyam D
authors.initials: GD
authors.lastname: Ghadge
authors.forename: Morton F
authors.initials: MF
authors.lastname: Arnsdorf
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Roos
authors.forename: Ratnesh
authors.initials: R
authors.lastname: Lal
mesh_terms: D000409:Alanine / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D055592:Biophysical Phenomena / Q000235:genetics; D001703:Biophysics / Q000379:methods; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D004558:Electric Stimulation; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics*; D008051:Lipid Bilayers; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D008567:Membranes, Artificial; D051379:Mice; D018625:Microscopy, Atomic Force; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology; D018408:Patch-Clamp Techniques; D011487:Protein Conformation; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014633:Valine / Q000235:genetics
chemical_list: D008051:Lipid Bilayers; D008567:Membranes, Artificial; D013482:Superoxide Dismutase; D014633:Valine; D000409:Alanine; D002118:Calcium