Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism

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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Publication Details

Journal
Acta Neuropathologica Communications
Published
2025-05-22
DOI
https://doi.org/10.1186/s40478-025-02039-3
Citations
4
Primary Topic
Genetic Neurodegenerative Diseases
Type
article
Field-Weighted Citation Impact
3.64

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article

Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism

Derek P. Narendra, Sandra Harjuhaahto, Pekka Katajisto, Emilia Kuuluvainen et al.
4 citations
Acta Neuropathologica Communications
Genetic Neurodegenerative Diseases
3.64
article

Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism

Derek P. Narendra, Sandra Harjuhaahto, Pekka Katajisto, Emilia Kuuluvainen, Annakaisa Haapasalo, Ville Hietakangas, Emil Ylikallio, Eija Pirinen, Kimmo Haimilahti, Satu Kuure, Bowen Hu, Tomáš Zárybnický, Sanna‐Kaisa Herukka, Liliya Euro, Manu Jokela, Ludo Van Den Bosch, Jouni Kvist, Jayasimman Rajendran, Henna Tyynismaa, Thibaut Burg, Xiaoping Huang, Fuping Zhang, S. Gopalakrishnan, Nadine Huber, Minea Rokka
article en
4 citations

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.

Acta Neuropathologica CommunicationsVol. 13(1)
University of Helsinki (FI), University of Eastern Finland (FI), Oulu University Hospital (FI), Helsinki Institute of Physics (FI), Helsinki University Hospital (FI), Turku University Hospital (FI), Karolinska Institutet (SE), Kuopio University Hospital (FI), National Institute of Neurological Disorders and Stroke (US), Tampere University Hospital (FI), Tampere University (FI), Institute for Molecular Medicine Finland (FI), VIB-KU Leuven Center for Brain & Disease Research (BE), University of Oulu (FI)
Helsingin Yliopisto, Helsingin ja Uudenmaan Sairaanhoitopiiri, Biomedicum Helsinki-säätiö, Magnus Ehrnroothin Säätiö, Päivikki ja Sakari Sohlbergin Säätiö, Emil Aaltosen Säätiö, Orionin Tutkimussäätiö, Biocenter Finland
Zero hunger
Openalex Percentile: Top 7%
Genetic Neurodegenerative Diseases
3.64
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