The legs at odd angles (Loa) mutation in cytoplasmic dynein ameliorates mitochondrial function in SOD1G93A mouse model for motor neuron disease.
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute approximately 10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15-20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1(G93A). In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1(G93A) motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1(G93A) motor neurons.
El-Kadi
Ali Morsi
AM
Biochemistry and Biomedical Science, School of Life Sciences, University of Sussex, Brighton BN1 9QG, United Kingdom.
Bros-Facer
Virginie
V
Deng
Wenhan
W
Philpott
Amelia
A
Stoddart
Eleanor
E
Banks
Gareth
G
Jackson
Graham S
GS
Fisher
Elizabeth M C
EM
Duchen
Michael R
MR
Greensmith
Linda
L
Moore
Anthony L
AL
Hafezparast
Majid
M
D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D004398:Dyneins / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D016472:Motor Neuron Disease / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D004398:Dyneins
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