ARM is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). He also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic (ARRNC), University of Edinburgh, and a seedcorn grant from The Chief Scientist Office and the RS Macdonald Charitable Trust via the Scottish Neurological Research Fund, administered by the University of St Andrews. JMG is funded by a starter grant for clinical lecturers from the Academy of Medical Sciences. CS is supported by a Medical Research Council grant (MR/L016400/1). NMM was funded by a Wellcome Trust New Investigator Award (100981/Z/13/Z). RNC and NMM are funded by a Diabetes UK grant (17/0005697). The Hardingham and Chandran laboratories are supported by the Euan MacDonald Centre for Motor Neurone Disease Research, and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd, funded by the MRC, Alzheimer's Society and Alzheimer's Research UK. SC also acknowledges funding from the ARRNC, My Name’5 Doddie Foundation, and an MRC Dementias Platform UK Stem Cell Partnership grant (MR/N013255/1). BTS is a Rowling-DRI Fellow.Peer reviewedPublisher PD

Burr, Karen

Carter, Roderick N.

Chandran, Siddharthan

Dando, Owen

Gregory, Jenna M.

Hardingham, Giles E.

Mahad, Don J.

Mcdade, Karina

Mehta, Arpan R.

Morton, Nicholas M.

Nanda, Jyoti

Selvaraj, Bhuvaneish T.

Smith, Colin

Story, David

Acta Neuropathologica

English

Edinburgh Research Explorer

Axonal dysfunction is a common phenotype in neurodegenerative disorders, including in amyotrophic lateral sclerosis (ALS), where the key pathological cell-type, the motor neuron (MN), has an axon extending up to a metre long. The maintenance of axonal function is a highly energy-demanding process, raising the question of whether MN cellular energetics is perturbed in ALS, and whether its recovery promotes axonal rescue. To address this, we undertook cellular and molecular interrogation of multiple patient-derived induced pluripotent stem cell lines and patient autopsy samples harbouring the most common ALS causing mutation, C9orf72. Using paired mutant and isogenic expansion-corrected controls, we show that C9orf72 MNs have shorter axons, impaired fast axonal transport of mitochondrial cargo, and altered mitochondrial bioenergetic function. RNAseq revealed reduced gene expression of mitochondrially encoded electron transport chain transcripts, with neuropathological analysis of C9orf72-ALS post-mortem tissue importantly confirming selective dysregulation of the mitochondrially encoded transcripts in ventral horn spinal MNs, but not in corresponding dorsal horn sensory neurons, with findings reflected at the protein level. Mitochondrial DNA copy number was unaltered, both in vitro and in human post-mortem tissue. Genetic manipulation of mitochondrial biogenesis in C9orf72 MNs corrected the bioenergetic deficit and also rescued the axonal length and transport phenotypes. Collectively, our data show that loss of mitochondrial function is a key mediator of axonal dysfunction in C9orf72-ALS, and that boosting MN bioenergetics is sufficient to restore axonal homeostasis, opening new potential therapeutic strategies for ALS that target mitochondrial function.</p

McDade, Karina

University of Dundee Online Publications

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis

ARM is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). He also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic (ARRNC), University of Edinburgh, and a seedcorn grant from The Chief Scientist Office and the RS Macdonald Charitable Trust via the Scottish Neurological Research Fund, administered by the University of St Andrews. JMG is funded by a starter grant for clinical lecturers from the Academy of Medical Sciences. CS is supported by a Medical Research Council grant (MR/L016400/1). NMM was funded by a Wellcome Trust New Investigator Award (100981/Z/13/Z). RNC and NMM are funded by a Diabetes UK grant (17/0005697). The Hardingham and Chandran laboratories are supported by the Euan MacDonald Centre for Motor Neurone Disease Research, and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd, funded by the MRC, Alzheimer's Society and Alzheimer's Research UK. SC also acknowledges funding from the ARRNC, My Name’5 Doddie Foundation, and an MRC Dementias Platform UK Stem Cell Partnership grant (MR/N013255/1). BTS is a Rowling-DRI Fellow.Peer reviewe

Gregory, Jenna

Aberdeen University Research

https://www.research.ed.ac.uk/portal/files/188892069/Mehta2021_Article_MitochondrialBioenergeticDefic.pdf

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis

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