Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism
Harjuhaahto, Sandra; Jokela, Manu; Rajendran, Jayasimman; Rokka, Minea; Hu, Bowen; Kvist, Jouni; Zhang, Fuping; Zárybnický, Tomáš; Haimilahti, Kimmo; Euro, Liliya; Pirinen, Eija; Huber, Nadine; Herukka, Sanna-Kaisa; Haapasalo, Annakaisa; Kuuluvainen, Emilia; Gopalakrishnan, Swetha; Katajisto, Pekka; Hietakangas, Ville; Burg, Thibaut; Van Den Bosch, Ludo; Huang, Xiaoping; Narendra, Derek P; Kuure, Satu; Ylikallio, Emil; Tyynismaa, Henna (2025-05-22)
Biomed central
22.05.2025
Harjuhaahto, S., Jokela, M., Rajendran, J. et al. Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism. acta neuropathol commun 13, 111 (2025). https://doi.org/10.1186/s40478-025-02039-3
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https://creativecommons.org/licenses/by-nc-nd/4.0/
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
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Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202505233883
https://urn.fi/URN:NBN:fi:oulu-202505233883
Tiivistelmä
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.
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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- Avoin saatavuus [38506]
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