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Original research
Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice
  1. Emily P McCann1,
  2. Jennifer A Fifita1,
  3. Natalie Grima1,
  4. Jasmin Galper1,
  5. Prachi Mehta1,
  6. Sarah E Freckleton1,
  7. Katharine Y Zhang1,
  8. Lyndal Henden1,
  9. Alison L Hogan1,
  10. Sandrine Chan Moi Fat1,
  11. Sharlynn SL Wu1,
  12. Cyril J Jagaraj1,
  13. Britt A Berning2,
  14. Kelly Louise Williams1,
  15. Natalie A Twine1,3,
  16. Denis Bauer3,
  17. Olivier Piguet4,
  18. John Hodges4,
  19. John B J Kwok4,
  20. Glenda M Halliday4,
  21. Matthew C Kiernan4,
  22. Julie Atkin1,
  23. Dominic B Rowe1,5,
  24. Garth A Nicholson1,6,7,8,
  25. Adam K Walker1,2,
  26. Ian P Blair1,
  27. Shu Yang1
  1. 1 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
  2. 2 Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
  3. 3 Commonwealth Scientific and Industrial Research Organization, Health & Biosecurity Flagship, Sydney, New South Wales, Australia
  4. 4 Brain and Mind Centre & Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
  5. 5 Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
  6. 6 Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia
  7. 7 Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
  8. 8 Molecular Medicine Laboratory, Concord Hospital, Sydney, New South Wales, Australia
  1. Correspondence to Prof Ian P Blair, Faculty of Medicine and Health Sciences, Centre for MND Research, Macquarie University, Sydney, NSW 2109, Australia; ian.blair{at}


Objective Since 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.

Methods Whole-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.

Results No 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.

Conclusions Genetic 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.

  • amyotrophic lateral sclerosis
  • coiled-coil-helix-coiled-coil-helix domain containing 10 protein
  • neuropathology
  • neurogenetics

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  • Twitter @NeuroBritt, @Dr_KLWilliams, @jnnp_bmj, @WalkerNeuroLab, @@BlairMNDgroup

  • EPM, JAF, IPB and SY contributed equally.

  • Correction notice This article has been corrected since it was published Online First. The funding statement has been amended, and ORCIDs added.

  • Contributors Study concept and design: EPM, JAF and SY with input from JA, AKW and IPB. Acquisition of data: major contribution from EPM, JAF, SY and NG and contributions from JG, SCMF, KLW, ALH, PM, SEF, KYZ, SSLW, CJJ and BAB. Analysis (including statistical) and interpretation of the data: EPM, JAF, NG, JG and SY. Data processing: NAT. Statistical analysis only: LH. Collection of clinical information and samples: OP, JH, JBJK, GMH, MCK, DBR and GAN. Study supervision: SY, DB, JA and IPB. Manuscript preparation: EPM, JAF, NG and SY. Critical revision of the manuscript: EPM, JAF, NG, SY, AKW, JA and IPB. All authors read and approved the final manuscript.

  • Funding This work was funded by Macquarie University (PhD scholarship to EPM), the Motor Neuron Disease Research Institute of Australia (Bill Gole Postdoctoral Research Fellowship to JAF, PhD scholarship top-up to EPM and BAB), MND Australia (Leadership Grant to IPB), the National Health and Medical Research Council of Australia (NHMRC)(grants 1095215, 1092023, 1124005 and RD Wright Career Development Fellowship 1140386 to AW), an Australian Government Research Training Program (scholarship to BAB), the Ross Maclean Fellowship and the Brazil Family Program for Neurology. The Brain and Mind Centre ALS and FTD cohorts were collected through Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, funded by the NHMRC (grants 1037746, 1095127 and 1132524). The Diamantina Control Cohort includes data obtained from projects funded by NHMRC Project Grants 1032571 and 511132. GMH is supported by a NHMRC Senior Principal Research Fellowship (grant 1079679). The postmortem brain tissue cohorts were collected by the New South Wales Brain Banks Network with the Sydney Brain Bank supported by the University of New South Wales and Neuroscience Research Australia and the New South Wales Brain Tissue Resource Centre supported by the National Institute on Alcohol Abuse and Alcoholism, NIHR28AA012725.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Animal Ethics Committee of Macquarie University (approval #2015-042).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request.