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

Abstract

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.

The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review

“…While mutations in Coiled‐Coil‐Helix‐Coiled‐Coil‐Helix Domain Containing 10 (CHCHD10) were not found to be common, reduced expression of CHCHD10 within neurons may have a role in the pathogenesis of sporadic ALS. 37 A genome‐wide gene expression study utilising brain materials from 113 individuals with a neurodegenerative condition did not identify commonly dysregulated genes suggesting mechanistically diverse pathogenesis. 39 …”

“…Neuropathological materials were used to confirm that several rare mutations including TANK‐binding kinase 1 (TBK1), 38 Profilin 1 (PNF1) 62,63 and Ataxin‐2 (ATXN2) 64 are neuropathologically associated with TDP‐43. While mutations in Coiled‐Coil‐Helix‐Coiled‐Coil‐Helix Domain Containing 10 (CHCHD10) were not found to be common, reduced expression of CHCHD10 within neurons may have a role in the pathogenesis of sporadic ALS 37 . A genome‐wide gene expression study utilising brain materials from 113 individuals with a neurodegenerative condition did not identify commonly dysregulated genes suggesting mechanistically diverse pathogenesis 39 …”

“…Neuropathological materials were used to confirm that several rare mutations including TANK-binding kinase 1 (TBK1), 38 Profilin 1 (PNF1) 62,63 and Ataxin-2 (ATXN2) 64 Coil-Helix Domain Containing 10 (CHCHD10) were not found to be common, reduced expression of CHCHD10 within neurons may have a role in the pathogenesis of sporadic ALS. 37 A genome-wide gene expression study utilising brain materials from 113 individuals with a neurodegenerative condition did not identify commonly dysregulated genes suggesting mechanistically diverse pathogenesis. 39 Increased activation of deoxyribonucleic acid (DNA) repair genes, 65 and deficits in homology-directed DNA repair pathways were identified in those with C9orf72 associated ALS.…”

Chchd10 is dispensable for myogenesis but critical for adipose browning

“…Previous work has indicated that CHCHD10 most likely functions as a chaperone for protein import. CHCHD10 is implicated in neurodegenerative diseases as inducing aggregation of TDP-43 (McCann et al 2020 ), a pathological feature of several neurodegenerative diseases (Woo et al 2017 ; Neumann et al 2007 ) Moreover, amyloid-like myo-granules were formed by TDP-43 and RNA in regenerating muscle (Vogler et al 2018 ). Our results also show that CHCHD10 interacts with TDP-43 in muscle cells, suggesting the possibility that CHCHD10 may transport TDP-43 into muscle cell nuclei.…”

Neurodegeneration-associated mitochondrial proteins, CHCHD2 and CHCHD10–what distinguishes the two?

“…Overexpression of the disease-associated CHCHD10 S59L causes mitochondrial fragmentation, loss, disassembly, and expansion of mitochondrial cristae (Bannwarth et al, 2014). In contrast, CHCHD10 protein levels were significantly lower in the spinal cord of patients with ALS and the frontal cortex of patients with frontotemporal lobe dementia (FTD) (McCann et al, 2020).…”