In Vivo Pathogenic Role of Mutant SOD1 Localized in the Mitochondrial Intermembrane Space

• Type of Material: Article
• Authors: Anissa Igoudjil, Cornell University; Jordi Magrane, Cornell University; Lindsey R. Fischer, Emory University; Hyun Jeong Kim, Cornell University; Isabel Hervias, Cornell University; Magali Dumont, Cornell University; Czrina Cortez, Cornell University; Jonathan D Glass, Emory University; Anatoly A. Starkov, Cornell University; Giovanni Manfredi, Cornell University
• Language: English
• Date: 2011-11-02
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: © 2011 the authors.
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.1965-11.2011
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 31
• Issue: 44
• Start Page: 15826
• End Page: 15837
• Grant/Funding Information: This work was supported by grants from The Robert Packard Center for ALS Research (to G.M. and J.M.); the Muscular Dystrophy Association (to J.M.); and the National Institutes of Health (Grants RO1-NS051419 and RO1-NS062055 to G.M.).
• Keywords: TRANSGENIC MICE; ALS; SUPEROXIDE-DISMUTASE; ACCUMULATION; AMYOTROPHIC-LATERAL-SCLEROSIS; PROTEIN; DEGENERATION; Life Sciences & Biomedicine; Neurosciences & Neurology; Science & Technology; HUMAN-CELLS; MOUSE MODEL; MOTOR-NEURON DISEASE; Neurosciences
• Research Categories: Biology, Cell; Biology, Neuroscience

Abstract

Mutations in Cu,Zn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 causes a complex array of pathological events, through toxic gain of function mechanisms, leading to selective motor neuron degeneration. Mitochondrial dysfunction is among the well established toxic effects of mutant SOD1, but its mechanisms are just starting to be elucidated. A portion of mutant SOD1 is localized in mitochondria, where it accumulates mostly on the outer membrane and inside the intermembrane space (IMS). Evidence in cultured cells suggests that mutant SOD1 in the IMS causes mitochondrial dysfunction and compromises cell viability. Therefore, to test its pathogenic role in vivo we generated transgenic mice expressing G93A mutant or wild-type (WT) human SOD1 targeted selectively to the mitochondrial IMS (mito-SOD1). We show that mito-SOD1 is correctly localized in the IMS, where it oligomerizes and acquires enzymatic activity. Mito-G93ASOD1 mice, but not mito-WTSOD1 mice, develop a progressive disease characterized by body weight loss, muscle weakness, brain atrophy, and motor impairment, which is more severe in females. These symptoms are associated with reduced spinal motor neuron counts and impaired mitochondrial bioenergetics, characterized by decreased cytochrome oxidase activity and defective calcium handling. However, there is no evidence of muscle denervation, a cardinal pathological feature of ALS. Together, our findings indicate that mutant SOD1 in the mitochondrial IMS causes mitochondrial dysfunction and neurodegeneration, but per se it is not sufficient to cause a full-fledged ALS phenotype, which requires the participation of mutant SOD1 localized in other cellular compartments.