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The Legs at odd angles (Loa) mutation in cytoplasmic dynein ameliorates mitochondrial function in SOD1G93A mouse model for motor neuron disease.

journal contribution
posted on 2023-06-07, 22:11 authored by Ali Morsi el Kadi, Virginie Bros-Facer, Wenhan Deng, Amelia Philpott, Eleanor Stoddart, Gareth Banks, Graham S Jackson, Elizabeth M C Fisher, Michael R Duchen, Linda Greensmith, Anthony Moore, Majid HafezparastMajid Hafezparast
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ~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 SOD1G93A. 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 SOD1G93A 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 SOD1G93A motor neurons.

History

Publication status

  • Published

Journal

Journal of Biological Chemistry

ISSN

1083-351X

Publisher

American Society for Biochemistry and Molecular Biology

Issue

24

Volume

285

Page range

18627-18639

Pages

13.0

Department affiliated with

  • Neuroscience Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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