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

• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0022031

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.