Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity

Abstract

Although multiple CHCHD10 mutations are associated with the spectrum of familial and sporadic frontotemporal dementia–amyotrophic lateral sclerosis (FTD–ALS) diseases, neither the normal function of endogenous CHCHD10 nor its role in the pathological milieu (that is, TDP-43 pathology) of FTD/ALS have been investigated. In this study, we made a series of observations utilizing Caenorhabditis elegans models, mammalian cell lines, primary neurons and mouse brains, demonstrating that CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43, whereas FTD/ALS-associated mutations (R15L and S59L) exhibit loss of function phenotypes in C. elegans genetic complementation assays and dominant negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation. As such, our results provide a pathological link between CHCHD10-associated mitochondrial/synaptic dysfunction and cytoplasmic TDP-43 inclusions.

A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

“…Even stronger clustering was observed for G66V and E127K in nearly all cells. Other variants in the hydrophobic domain had little (G58R and G66S) or no effect (V57E) on CHCHD10 localization but may have subtle effects on mitochondrial morphology similar to reports for S59L (Bannwarth et al , ; Woo et al , ). The other variants showed no gross abnormalities in expression level and localization by immunofluorescence (Fig EV3), highlighting the importance of the hydrophobic region and the CHCH domain.…”

“…Patient fibroblasts with the S59L mutation show an altered mitochondrial network structure, but as mitochondrial fusion is normal, this may be secondary to instability of mitochondrial DNA (Bannwarth et al , ). Overexpression of human wild‐type but not R15L or S59L CHCHD10 rescues the shorter lifespan of Caenorhabditis elegans lacking the CHCHD10 homolog har‐1 (Woo et al , ). The reported inhibition of apoptosis by CHCHD10 S59L (Genin et al , ) has not been replicated by others (Woo et al , ) and is difficult to reconcile with a neurodegenerative process.…”

“…Overexpression of human wild‐type but not R15L or S59L CHCHD10 rescues the shorter lifespan of Caenorhabditis elegans lacking the CHCHD10 homolog har‐1 (Woo et al , ). The reported inhibition of apoptosis by CHCHD10 S59L (Genin et al , ) has not been replicated by others (Woo et al , ) and is difficult to reconcile with a neurodegenerative process. The neuropathological features of CHCHD10 cases have not been comprehensively characterized, but CHCHD10 was recently linked to synaptic integrity and nuclear retention of TDP‐43 (Woo et al , ), although the latter has not been replicated (Brockmann et al , ).…”

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

“…In the nucleus CHCHD10 colocalizes with DAPI as suggested by a positive Pearson correlation coefficient. A recent study also showed nuclear localization (21). We further validated the nuclear signal by use of a stable knockdown of CHCHD10 in HEK293 cells (Fig.…”

“…Thus, even in the presence of elevated levels of MNRR1 the two mutant versions of CHCHD10 prevent phosphorylation of MNRR1, giving rise to the mitochondrial phenotype seen. A recent study also showed that CHCHD10 is localized to both the mitochondria and the nucleus and that its normal function prevents the neurotoxic mitochondrial localization of the protein TDP-43 whereas two other disease associated mutations, R15L and S59L, promote its cytoplasmic mislocalization (21). These mutations have also been shown to accumulate excessive mitochondrial iron (37).…”