• Emily P McCann, Jennifer A Fifita, Natalie Grima, Jasmin Galper, Prachi Mehta, Sarah E Freckleton, Katharine Y Zhang, Lyndal Henden, Alison L Hogan, Sandrine Chan Moi Fat, Sharlynn Sl Wu, Cyril J Jagaraj, Britt A Berning, Kelly Louise Williams, Natalie A Twine, Denis Bauer, Olivier Piguet, John Hodges, Kwok John B J JBJ Brain and Mind Centre & Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Glenda M Halliday, Matthew C Kiernan, Julie Atkin, Dominic B Rowe, Garth A Nicholson, Adam K Walker, Ian P Blair, and Shu Yang.
• Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
• J. Neurol. Neurosurg. Psychiatr. 2020 Feb 1; 91 (2): 162-171.

ObjectiveSince the first report of CHCHD10 gene mutations in amyotrophiclateral sclerosis (ALS)/frontotemporaldementia (FTD) patients, genetic variation in CHCHD10 has been inconsistently linked to disease. A pathological assessment of the CHCHD10 protein in patient neuronal tissue also remains to be reported. We sought to characterise the genetic and pathological contribution of CHCHD10 to ALS/FTD in Australia.MethodsWhole-exome and whole-genome sequencing data from 81 familial and 635 sporadic ALS, and 108 sporadic FTD cases, were assessed for genetic variation in CHCHD10. CHCHD10 protein expression was characterised by immunohistochemistry, immunofluorescence and western blotting in control, ALS and/or FTD postmortem tissues and further in a transgenic mouse model of TAR DNA-binding protein 43 (TDP-43) pathology.ResultsNo causal, novel or disease-associated variants in CHCHD10 were identified in Australian ALS and/or FTD patients. In human brain and spinal cord tissues, CHCHD10 was specifically expressed in neurons. A significant decrease in CHCHD10 protein level was observed in ALS patient spinal cord and FTD patient frontal cortex. In a TDP-43 mouse model with a regulatable nuclear localisation signal (rNLS TDP-43 mouse), CHCHD10 protein levels were unaltered at disease onset and early in disease, but were significantly decreased in cortex in mid-stage disease.ConclusionsGenetic variation in CHCHD10 is not a common cause of ALS/FTD in Australia. However, we showed that in humans, CHCHD10 may play a neuron-specific role and a loss of CHCHD10 function may be linked to ALS and/or FTD. Our data from the rNLS TDP-43 transgenic mice suggest that a decrease in CHCHD10 levels is a late event in aberrant TDP-43-induced ALS/FTD pathogenesis.© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

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