CHCHD2 and CHCHD10: Future therapeutic targets in cognitive disorder and motor neuron disorder

Jiang, Tianlin; Wang, Yanli; Wang, Xiaohong; Xu, Jun

doi:10.3389/fnins.2022.988265

Cited by 9 publications

(6 citation statements)

References 48 publications

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“…Many people with FTDALS2 also suffer from frontotemporal dementia but display many other aspects, including cerebellar ataxia, myopathy, motor neuron disease, and late-onset neurodegenerative diseases, similar to ALS. FTDALS2 is responsible for an amino acid replacement mutation of the mitochondrial coiled-coil-helix-coiled-coil-helix domain containing protein 10 (CHCHD10) [47,48]. As such, although FTDALSs involve a variety of symptoms and many responsible genes, they are considered to be classified as a single disease.…”

Section: Discussionmentioning

confidence: 99%

Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr

Fukatsu,

Okawa,

Okabe

et al. 2024

CIMB

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Some charged multivesicular body protein 2B (CHMP2B) mutations are associated with autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTDALS7). The main aim of this study is to clarify the relationship between the expression of mutated CHMP2B protein displaying FTD symptoms and defective neuronal differentiation. First, we illustrate that the expression of CHMP2B with the Asp148Tyr (D148Y) mutation, which preferentially displays FTD phenotypes, blunts neurite process elongation in rat primary cortical neurons. Similar results were observed in the N1E-115 cell line, a model that undergoes neurite elongation. Second, these effects were also accompanied by changes in neuronal differentiation marker protein expression. Third, wild-type CHMP2B protein was indeed localized in the endosomal sorting complexes required to transport (ESCRT)-like structures throughout the cytoplasm. In contrast, CHMP2B with the D148Y mutation exhibited aggregation-like structures and accumulated in the Golgi body. Fourth, among currently known Golgi stress regulators, the expression levels of Hsp47, which has protective effects on the Golgi body, were decreased in cells expressing CHMP2B with the D148Y mutation. Fifth, Arf4, another Golgi stress-signaling molecule, was increased in mutant-expressing cells. Finally, when transfecting Hsp47 or knocking down Arf4 with small interfering (si)RNA, cellular phenotypes in mutant-expressing cells were recovered. These results suggest that CHMP2B with the D148Y mutation, acting through Golgi stress signaling, is negatively involved in the regulation of neuronal cell morphological differentiation, providing evidence that a molecule controlling Golgi stress may be one of the potential FTD therapeutic targets at the molecular and cellular levels.

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Section: Discussionmentioning

confidence: 99%

Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr

Fukatsu,

Okawa,

Okabe

et al. 2024

CIMB

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“…Moreover, CHCHD10 is involved in regulating mitochondrial structure and function [21]. Frontotemporal dementia, a rare neurodegenerative disorder, and cardiovascular diseases are linked to mutations in the CHCHD10 gene [22,23]. CHCHD2 and CHCHD10 genes play crucial roles in maintaining the health and functionality of mitochondria, which is essential for cellular metabolism [24,25].…”

Section: Discussionmentioning

confidence: 99%

A Mendelian randomization study identifies the causal association between plasma mitochondrial CHCHD proteins and polycystic ovary syndrome

Wei,

Wang,

Liu

et al. 2024

Preprint

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PurposeThe objective of this research was to examine the causal link between PCOS and plasma mitochondrial coiled-coil-helix-coiled-coil-helix domain(CHCHD) proteins using a Mendelian randomization (MR) method.MethodsWe performed a two-sample MR analyses by utilizing summary statistics obtained from genome-wide association studies (GWAS) of PCOS (642 cases and 118,228 controls) and the levels of CHCHD2 and CHCHD10 in plasma (3,301 individuals). The inverse-variance weighted (IVW) method was used for the MR analyses, along with additional sensitivity analyses.ResultsThe association between CHCHD2 and an increased risk of PCOS was identified (OR = 1.682; 95% CI = (1.231, 2.297); P = 0.001). The discovery of CHCHD10 revealed a protective impact on the likelihood of PCOS (OR = 0.828, 95% CI= 0.698-0.981, p = 0.029). The MR results were confirmed to be robust through the analysis of heterogeneity (P > 0.05) and pleiotropy (P > 0.05).ConclusionOur findings indicates that mitochondrial proteins CHCHD2 and CHCHD10 may play an important role in the pathogenesis of PCOS. Additional research is necessary to clarify the underlying mechanisms and investigate the potential of these proteins as targets for therapeutic intervention in PCOS.What does this study add to the clinical workA strong causal relationship has been established between two plasma mitochondrial complexes with coiled-coil-helix domains and polycystic ovary syndrome. The exact role of serum mitochondrial protein in polycystic ovary syndrome needs to be investigated via large-scale randomization trials or further studies.

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“…In addition, mitophagy, a specialized form of autophagy concerning mitocondria, is carried out by the interaction of TBK1 , PRKN and OPTN ( Harding et al, 2021 ). Mitochondrial homeostasis is the function of CHCHD10 , linked to FTD, ALS and PD ( Jiang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort

Rossi

Mehmeti

Ricci

et al. 2022

Front. Aging Neurosci.

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Semantic and right temporal variant of frontotemporal dementia (svFTD and rtvFTD) are rare clinical phenotypes in which, in most cases, the underlying pathology is TDP-43 proteinopathy. They are usually sporadic disorders, but recent evidences suggest a higher frequency of genetic mutations for the right temporal versus the semantic variant. However, the genetic basis of these forms is not clear. In this study we performed a genetic screening of a single-center cohort of svFTD and rtvFTD patients, aiming at identifying the associated genetic variants. A panel of 73 dementia candidate genes has been analyzed by NGS target sequencing including both causal and risk/modifier genes in 23 patients (15 svFTD and 8 rtvFTD) and 73 healthy age-matched controls. We first performed a single variant analysis considering rare variants and then a gene-based aggregation analysis to evaluate the cumulative effects of multiple rare variants in a single gene. We found 12 variants in nearly 40% of patients (9/23), described as pathogenic or classified as VUS/likely pathogenic. The overall rate was higher in svFTD than in rtvFTD. Three mutations were located in MAPT gene and single mutations in the following genes: SQSTM1, VCP, PSEN1, TBK1, OPTN, CHCHD10, PRKN, DCTN1. Our study revealed the presence of variants in genes involved in pathways relevant for the pathology, especially autophagy and inflammation. We suggest that molecular analysis should be performed in all svFTD and rtvFTD patients, to better understand the genotype–phenotype correlation and the pathogenetic mechanisms that could drive the clinical phenotypes in FTD.

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CHCHD2 and CHCHD10: Future therapeutic targets in cognitive disorder and motor neuron disorder

Cited by 9 publications

References 48 publications

Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr

Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr

A Mendelian randomization study identifies the causal association between plasma mitochondrial CHCHD proteins and polycystic ovary syndrome

Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort

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