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

• Published in: iScience 2021-02, Vol.24 (2), p.102061-102061, Article 102061
• Main Authors: Ryan, Éanna B., Yan, Jianhua, Miller, Nimrod, Dayanidhi, Sudarshan, Ma, Yongchao C., Deng, Han-Xiang, Siddique, Teepu
• Format: Article
• Language: English
• Subjects: Molecular Biology; Molecular Physiology; Neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.102061

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. [Display omitted] •Transgenic mice expressing wild-type or ALS-linked CHCHD10 p.R15L developed•CHCHD10-R15L mice display widespread axonal swellings in the CNS•Mice perform well in motor tests despite CNS, skeletal muscle, and cardiac pathology•Early death of CHCHD10-R15L mice likely due to cardiac failure Molecular Physiology; Molecular Biology; Neuroscience