ArticleActa neuropathologica communications2025
Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.
Article in Acta neuropathologica communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- Junctions in Jeopardy: the neuromuscular junction is a selective pathological target in Charcot-Marie-Tooth disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.Amino acids · 2026Review
- Multiomics profiling of zebrafish embryonic cell line PAC2 across growth phases to assess its relevance for toxicological studies.PloS one · 2026Article
- Clinical, neuropathological, and biochemical characterization of ALS in a large CHCHD10 R15L family.medRxiv : the preprint server for health sciences · 2025Article
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25 authors.
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Abstract
Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant are less clear. Here we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ. We demonstrate that the amount of the mutant CHCHD10 is reduced, but the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state. Novel knock-in mouse model recapitulates the dose-dependent reduction of mutant CHCHD10 protein and the slow disease progression of SMAJ. With metabolome analysis of patients' primary fibroblasts and patient-specific motor neurons, we show that CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism.
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