Early death of ALS-linked CHCHD10-R15L transgenic mice with central nervous system, skeletal muscle, and cardiac pathology

Éanna B. Ryan; Jianhua Yan; Nimrod Miller; Sudarshan Dayanidhi; Yongchao C. Ma; Han Xiang Deng; Teepu Siddique

doi:10.1016/j.isci.2021.102061

Early death of ALS-linked CHCHD10-R15L transgenic mice with central nervous system, skeletal muscle, and cardiac pathology

Éanna B. Ryan, Jianhua Yan, Nimrod Miller, Sudarshan Dayanidhi, Yongchao C. Ma, Han Xiang Deng, Teepu Siddique^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) have been identified in patients suffering from various degenerative diseases including mitochondrial myopathy, spinal muscular atrophy Jokela type, frontotemporal dementia, and/or amyotrophic lateral sclerosis (ALS). The pathogenic mechanism underlying CHCHD10-linked divergent disorders remains largely unknown. Here we show that transgenic mice overexpressing an ALS-linked CHCHD10 p.R15L mutation leads to an abbreviated lifespan compared with CHCHD10-WT transgenic mice. The occurrence and severity of the phenotype correlates to transgene copy number. Central nervous system (CNS), skeletal muscle, and cardiac pathology is apparent in CHCHD10-R15L transgenic mice. Despite the pathology, CHCHD10-R15L transgenic mice perform comparably to control mice in motor behavioral tasks until very close to death. Although paralysis is not observed, these models provide insight into the pleiotropic nature of CHCHD10 and suggest a contribution of CNS, skeletal muscle, and cardiac pathology to CHCHD10 p.R15L-ALS pathogenesis.

Original language	English (US)
Article number	102061
Journal	iScience
Volume	24
Issue number	2
DOIs	https://doi.org/10.1016/j.isci.2021.102061
State	Published - Feb 19 2021

Funding

This study was supported by the National Institute of Neurological Disorders and Stroke ( NS099638 ), the Foglia Family Foundation, the Les Turner ALS Foundation, and the Les Turner ALS Foundation/Herbert C. Wenske Foundation Professorship. The genetically engineered mice were generated with the assistance of the Northwestern University Transgenic and Targeted Mutagenesis Laboratory, which is partially supported by NIH grant CA60553 to the Robert H. Lurie Comprehensive Cancer Center. Open Field and DigiGait testing of mice was performed at the Northwestern University Behavioral Phenotyping Core Facility. Tissue embedding work was supported by the Northwestern University Pathology Core Facility and a Cancer Center Support Grant ( NCI CA060553 ). Confocal and electron microscopy imaging was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Echocardiography research was supported by George M. O'Brien Kidney Research Core Center (NU GoKidney), which is generously supported by the award P30 DK114857 from the National Institute of Diabetes and Digestive and Kidney Diseases , within the National Institutes of Health. We thank Dr. Erdong Liu, Ms Hong Zhai, and Ms Michele Hadhazy for technical assistance. We thank Dr. Jon Lomasney and Dr. Alexis Demonbreun for assistance with data analysis.

Keywords

Molecular Biology
Molecular Physiology
Neuroscience

ASJC Scopus subject areas

General

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title = "Early death of ALS-linked CHCHD10-R15L transgenic mice with central nervous system, skeletal muscle, and cardiac pathology",

abstract = "Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) have been identified in patients suffering from various degenerative diseases including mitochondrial myopathy, spinal muscular atrophy Jokela type, frontotemporal dementia, and/or amyotrophic lateral sclerosis (ALS). The pathogenic mechanism underlying CHCHD10-linked divergent disorders remains largely unknown. Here we show that transgenic mice overexpressing an ALS-linked CHCHD10 p.R15L mutation leads to an abbreviated lifespan compared with CHCHD10-WT transgenic mice. The occurrence and severity of the phenotype correlates to transgene copy number. Central nervous system (CNS), skeletal muscle, and cardiac pathology is apparent in CHCHD10-R15L transgenic mice. Despite the pathology, CHCHD10-R15L transgenic mice perform comparably to control mice in motor behavioral tasks until very close to death. Although paralysis is not observed, these models provide insight into the pleiotropic nature of CHCHD10 and suggest a contribution of CNS, skeletal muscle, and cardiac pathology to CHCHD10 p.R15L-ALS pathogenesis.",

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AU - Siddique, Teepu

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Early death of ALS-linked CHCHD10-R15L transgenic mice with central nervous system, skeletal muscle, and cardiac pathology

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