title: Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis.
abstract: Mitochondria have been proposed as targets for toxicity in amyotrophic lateral sclerosis (ALS), a progressive, fatal adult-onset neurodegenerative disorder characterized by the selective loss of motor neurons. A decrease in the capacity of spinal cord mitochondria to buffer calcium (Ca(2+)) has been observed in mice expressing ALS-linked mutants of SOD1 that develop motor neuron disease with many of the key pathological hallmarks seen in ALS patients. In mice expressing three different ALS-causing SOD1 mutants, we now test the contribution of the loss of mitochondrial Ca(2+)-buffering capacity to disease mechanism(s) by eliminating ubiquitous expression of cyclophilin D, a critical regulator of Ca(2+)-mediated opening of the mitochondrial permeability transition pore that determines mitochondrial Ca(2+) content. A chronic increase in mitochondrial buffering of Ca(2+) in the absence of cyclophilin D was maintained throughout disease course and was associated with improved mitochondrial ATP synthesis, reduced mitochondrial swelling, and retention of normal morphology. This was accompanied by an attenuation of glial activation, reduction in levels of misfolded SOD1 aggregates in the spinal cord, and a significant suppression of motor neuron death throughout disease. Despite this, muscle denervation, motor axon degeneration, and disease progression and survival were unaffected, thereby eliminating mutant SOD1-mediated loss of mitochondrial Ca(2+) buffering capacity, altered mitochondrial morphology, motor neuron death, and misfolded SOD1 aggregates, as primary contributors to disease mechanism for fatal paralysis in these models of familial ALS.
authors.affiliation: Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Parone
authors.forename: Sandrine
authors.initials: S
authors.lastname: Da Cruz
authors.forename: Joo Seok
authors.initials: JS
authors.lastname: Han
authors.forename: Melissa
authors.initials: M
authors.lastname: McAlonis-Downes
authors.forename: Anne P
authors.initials: AP
authors.lastname: Vetto
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Lee
authors.forename: Eva
authors.initials: E
authors.lastname: Tseng
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001369:Axons / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002850:Chromatography, Gel; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000473:pathology* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: C491049:Aif1 protein, mouse; D000906:Antibodies; D002135:Calcium-Binding Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; C000631446:PPIF protein, mouse; C000606290:SOD1 protein, human; D000255:Adenosine Triphosphate; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D021983:Cyclophilins; D002118:Calcium