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

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

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 vari...

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Main Authors: Sandra Harjuhaahto, Manu Jokela, Jayasimman Rajendran, Minea Rokka, Bowen Hu, Jouni Kvist, Fuping Zhang, Tomáš Zárybnický, Kimmo Haimilahti, Liliya Euro, Eija Pirinen, Nadine Huber, Sanna-Kaisa Herukka, Annakaisa Haapasalo, Emilia Kuuluvainen, Swetha Gopalakrishnan, Pekka Katajisto, Ville Hietakangas, Thibaut Burg, Ludo Van Den Bosch, Xiaoping Huang, Derek P. Narendra, Satu Kuure, Emil Ylikallio, Henna Tyynismaa
Format: Article
Language:English
Published: BMC 2025-05-01
Series:Acta Neuropathologica Communications
Subjects:
CHCHD10
CHCHD2
ALS
Mitochondria
Creatine
Metabolomics
Online Access:https://doi.org/10.1186/s40478-025-02039-3
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Summary: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.
ISSN:2051-5960

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