Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice

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 S. L. Wu, Cyril J. Jagaraj, Britt A. Berning, Kelly Louise Williams, Natalie A. Twine, Denis Bauer, Olivier Piguet, John Hodges, John B. J. Kwok, Glenda M. Halliday & 7 others Matthew C. Kiernan, Julie Atkin, Dominic B. Rowe, Garth A. Nicholson, Adam K. Walker, Ian P. Blair, Shu Yang

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

LanguageEnglish
JournalJournal of Neurology, Neurosurgery and Psychiatry
DOIs
Publication statusE-pub ahead of print - 5 Nov 2019

Fingerprint

Sclerosis
DNA-Binding Proteins
Transgenic Mice
Spinal Cord
Proteins
Exome
Frontotemporal Dementia With Motor Neuron Disease
mouse TDP-43 protein
Neurons
Nuclear Localization Signals
Frontal Lobe
Fluorescent Antibody Technique
Western Blotting
Immunohistochemistry
Genome
Pathology
Mutation
Brain

Keywords

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

Cite this

McCann, Emily P. ; Fifita, Jennifer A. ; Grima, Natalie ; Galper, Jasmin ; Mehta, Prachi ; Freckleton, Sarah E. ; Zhang, Katharine Y. ; Henden, Lyndal ; Hogan, Alison L. ; Chan Moi Fat, Sandrine ; Wu, Sharlynn S. L. ; Jagaraj, Cyril J. ; Berning, Britt A. ; Williams, Kelly Louise ; Twine, Natalie A. ; Bauer, Denis ; Piguet, Olivier ; Hodges, John ; Kwok, John B. J. ; Halliday, Glenda M. ; Kiernan, Matthew C. ; Atkin, Julie ; Rowe, Dominic B. ; Nicholson, Garth A. ; Walker, Adam K. ; Blair, Ian P. ; Yang, Shu. / Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice. In: Journal of Neurology, Neurosurgery and Psychiatry. 2019.
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title = "Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice",
abstract = "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.",
keywords = "amyotrophic lateral sclerosis, coiled-coil-helix-coiled-coil-helix domain containing 10 protein, neurogenetics, neuropathology",
author = "McCann, {Emily P.} and Fifita, {Jennifer A.} and Natalie Grima and Jasmin Galper and Prachi Mehta and Freckleton, {Sarah E.} and Zhang, {Katharine Y.} and Lyndal Henden and Hogan, {Alison L.} and {Chan Moi Fat}, Sandrine and Wu, {Sharlynn S. L.} and Jagaraj, {Cyril J.} and Berning, {Britt A.} and Williams, {Kelly Louise} and Twine, {Natalie A.} and Denis Bauer and Olivier Piguet and John Hodges and Kwok, {John B. J.} and Halliday, {Glenda M.} and Kiernan, {Matthew C.} and Julie Atkin and Rowe, {Dominic B.} and Nicholson, {Garth A.} and Walker, {Adam K.} and Blair, {Ian P.} and Shu Yang",
year = "2019",
month = "11",
day = "5",
doi = "10.1136/jnnp-2019-321790",
language = "English",
journal = "Journal of Neurology, Neurosurgery and Psychiatry",
issn = "0022-3050",
publisher = "B M J PUBLISHING GROUP",

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Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice. / McCann, Emily P.; Fifita, Jennifer A.; Grima, Natalie; Galper, Jasmin; Mehta, Prachi; Freckleton, Sarah E.; Zhang, Katharine Y.; Henden, Lyndal; Hogan, Alison L.; Chan Moi Fat, Sandrine; Wu, Sharlynn S. L.; Jagaraj, Cyril J.; Berning, Britt A.; Williams, Kelly Louise; Twine, Natalie A.; Bauer, Denis; Piguet, Olivier; Hodges, John; Kwok, John B. J.; Halliday, Glenda M.; Kiernan, Matthew C.; Atkin, Julie; Rowe, Dominic B.; Nicholson, Garth A.; Walker, Adam K.; Blair, Ian P.; Yang, Shu.

In: Journal of Neurology, Neurosurgery and Psychiatry, 05.11.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice

AU - McCann, Emily P.

AU - Fifita, Jennifer A.

AU - Grima, Natalie

AU - Galper, Jasmin

AU - Mehta, Prachi

AU - Freckleton, Sarah E.

AU - Zhang, Katharine Y.

AU - Henden, Lyndal

AU - Hogan, Alison L.

AU - Chan Moi Fat, Sandrine

AU - Wu, Sharlynn S. L.

AU - Jagaraj, Cyril J.

AU - Berning, Britt A.

AU - Williams, Kelly Louise

AU - Twine, Natalie A.

AU - Bauer, Denis

AU - Piguet, Olivier

AU - Hodges, John

AU - Kwok, John B. J.

AU - Halliday, Glenda M.

AU - Kiernan, Matthew C.

AU - Atkin, Julie

AU - Rowe, Dominic B.

AU - Nicholson, Garth A.

AU - Walker, Adam K.

AU - Blair, Ian P.

AU - Yang, Shu

PY - 2019/11/5

Y1 - 2019/11/5

N2 - 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.

AB - 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.

KW - amyotrophic lateral sclerosis

KW - coiled-coil-helix-coiled-coil-helix domain containing 10 protein

KW - neurogenetics

KW - neuropathology

UR - http://www.scopus.com/inward/record.url?scp=85074749459&partnerID=8YFLogxK

U2 - 10.1136/jnnp-2019-321790

DO - 10.1136/jnnp-2019-321790

M3 - Article

JO - Journal of Neurology, Neurosurgery and Psychiatry

T2 - Journal of Neurology, Neurosurgery and Psychiatry

JF - Journal of Neurology, Neurosurgery and Psychiatry

SN - 0022-3050

ER -