Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset

Mutations in superoxide dismutase (SOD1) are causative for inherited amyotrophic lateral sclerosis. A proportion of SOD1 mutant protein is misfolded onto the cytoplasmic face of mitochondria in one or more spinal cord cell types. By construction of mice in which mitochondrially targeted enhanced gre...

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Bibliographic Details
Published in:	PloS one Vol. 6; no. 7; p. e22031
Main Authors:	Vande Velde, Christine, McDonald, Karli K, Boukhedimi, Yasmin, McAlonis-Downes, Melissa, Lobsiger, Christian S, Bel Hadj, Samar, Zandona, Andre, Julien, Jean-Pierre, Shah, Sameer B, Cleveland, Don W
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 11-07-2011 Public Library of Science (PLoS)
Subjects:	Aberration Amyotrophic lateral sclerosis Animals Axon guidance Axons Biology Cancer Clustering Cytochrome Development and progression Elongation Fluorescence Fluorescent Antibody Technique Genetic aspects Green fluorescent protein Homeostasis Immunoblotting Medical research Medicine Mice Mice, Transgenic Mitochondria Mitochondria - metabolism Morphology Motor neurons Motor Neurons - metabolism Multiple sclerosis Mutation Neurons Neurosciences Pathogenesis Permeability Physical characteristics Protein Folding Recruitment Rodents Spinal cord Superoxide dismutase Superoxide Dismutase - chemistry Superoxide Dismutase - genetics Superoxide Dismutase - metabolism Superoxide Dismutase-1 Superoxides La Jolla California United States > US California
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Summary:	Mutations in superoxide dismutase (SOD1) are causative for inherited amyotrophic lateral sclerosis. A proportion of SOD1 mutant protein is misfolded onto the cytoplasmic face of mitochondria in one or more spinal cord cell types. By construction of mice in which mitochondrially targeted enhanced green fluorescent protein is selectively expressed in motor neurons, we demonstrate that axonal mitochondria of motor neurons are primary in vivo targets for misfolded SOD1. Mutant SOD1 alters axonal mitochondrial morphology and distribution, with dismutase active SOD1 causing mitochondrial clustering at the proximal side of Schmidt-Lanterman incisures within motor axons and dismutase inactive SOD1 producing aberrantly elongated axonal mitochondria beginning pre-symptomatically and increasing in severity as disease progresses. Somal mitochondria are altered by mutant SOD1, with loss of the characteristic cylindrical, networked morphology and its replacement by a less elongated, more spherical shape. These data indicate that mutant SOD1 binding to mitochondria disrupts normal mitochondrial distribution and size homeostasis as early pathogenic features of SOD1 mutant-mediated ALS.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: CVV DWC. Performed the experiments: CVV KKM YB SBH MM-D CSL AZ. Analyzed the data: CVV SBS DWC. Contributed reagents/materials/analysis tools: J-PJ SBS. Wrote the paper: CVV SBS DWC.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0022031