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.

Mitochondrial CHCHD2: Disease-Associated Mutations, Physiological Functions, and Current Animal Models

“…As mammals express both CHCHD2 and CHCHD10, genetic loss of either gene produces subtle to no phenotype (Burstein et al, 2018;Liu Y.T. et al, 2020;Ryan et al, 2021;Sato et al, 2021), likely due to redundancy and compensation. However, it was recently reported that CHCHD2 −/− mice show p62 inclusion formation and dopaminergic neuronal loss in an age-dependent manner (Sato et al, 2021).…”

“…Interestingly, CHCHD10 R15L transgenic mice die from cardiac failure because of the degeneration of cardiomyocytes. Despite these pathologies, CHCHD10 R15L transgenic mice do not exhibit paralysis or abnormal motor phenotypes (Ryan et al, 2021). Perhaps the divergent disease phenotypes between CHCHD2 mutations and CHCHD10 mutations may in part be explained by their ability to associate with different pathological proteins such as α-synuclein (Ikeda et al, 2019;Imai et al, 2019a) and TDP-43 (Woo et al, 2017;Genin et al, 2019;, respectively, the latter of which is a pathological hallmark of FTD-ALS (Neumann et al, 2006).…”

“…In mice, knockout of either CHCHD2 or CHCHD10 produce little to no gross abnormalities (Burstein et al, 2018;Liu Y.T. et al, 2020;Ryan et al, 2021;Sato et al, 2021). Homozygous CHCHD10 −/− mice are viable with no bioenergetic defects or mitochondrial abnormalities in dopaminergic processes in the brain, heart, and skeletal muscle (Burstein et al, 2018).…”

Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

“…CHCHD19 S55L knock-in mice were developed by two other independent groups [400,401]. Recently, Ryan and collaborators [402] generated transgenic mice overexpressing CHCHD10 R15L , which showed transgene copy-linked abbreviated lifespan compared with mice over expressing WT CHCHD10. However, CHCHD10 R15L mice performed comparably to control mice in motor behavioral tasks, without developing paralysis.…”

Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?

“…CHCHD10 encodes a mitochondrial protein, which may maintain the MICOS ( Genin et al, 2016 ). Mutant CHCHD10 is associated with mitochondrial dysfunction and the early death of motor neurons ( Ryan et al, 2021 ). In mutant CHCHD10 ALS mice, aggregation of mutant CHCHD10 induces proteotoxic stress and the upregulation of the UPR mt transcriptional regulators ATF5 and CHOP ( Anderson et al, 2019 ).…”