Modulation of synaptic plasticity, motor unit physiology, and TDP-43 pathology by CHCHD10

• Published in: Acta neuropathologica communications Vol. 10; no. 1; p. 95
• Main Authors: Liu, Tian, Woo, Jung-A A, Bukhari, Mohammed Zaheen, Wang, Xinming, Yan, Yan, Buosi, Sara Cazzaro, Ermekbaeva, Aizara, Sista, Apoorva, Kotsiviras, Peter, LePochat, Patrick, Chacko, Ann, Zhao, Xingyu, Kang, David E
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 04-07-2022; BioMed Central; BMC
• Subjects: Alzheimer's disease; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - pathology; Animals; Antibodies; Atomic force microscopy; Behavior; Brain; CHCHD10; Dementia; Development and progression; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Frontotemporal dementia; Frontotemporal Dementia - genetics; Frontotemporal Dementia - pathology; Humans; Mice; Mice, Transgenic; Microscopy; Mitochondria; Mitochondrial Proteins - genetics; Mutation; Neuronal Plasticity; Neurons; Pathology; Physiological aspects; Physiology; Proteins; Respiration; Synapse; TDP-43; Transgenic animals; United States > US; CHCHD10; Mitochondria; Synapse; Frontotemporal dementia; TDP-43
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-022-01386-9

Mutations in CHCHD10, a gene coding for a mitochondrial intermembrane space protein, are associated with Frontotemporal dementia (FTD)-Amyotrophic lateral sclerosis (ALS) spectrum disorders, which are pathologically characterized by cytoplasmic inclusions containing TDP-43. FTD/ALS-linked CHCHD10 mutations and TDP-43 inclusions similarly induce mitochondrial defects in respiration, fusion/fission, mtDNA stability, and cristae structure, while sizeable amounts of cytoplasmic TDP-43 aggregates are found in mitochondria. However, the mechanistic link between CHCHD10 and TDP-43 pathogenesis remains unclear. In this study, we present immunohistochemical and biochemical evidence demonstrating that insoluble CHCHD10 aggregates accumulate and colocalize with phospho-TDP-43 inclusions in brains of FTLD-TDP and AD patients, and that insoluble CHCHD10 levels tightly correlate with insoluble TDP-43 levels in control and FTLD-TDP brains. In an experimental exploration of this pathological phenotype, transgenic mice neuronally expressing FTD/ALS-linked CHCHD10
or CHCHD
mutations but not CHCHD10
transgenic mice exhibit significantly increased CHCHD10 aggregation and phospho-TDP-43 pathology, which often colocalize within the same inclusions. Such pathologies are reflected in poor functional outcomes in long-term synaptic plasticity, motor unit physiology, and behavior in CHCHD10
and CHCHD
transgenic mice. In contrast, expression of CHCHD10
in hTDP-43 transgenic mice (TAR4;CHCHD10
) significantly mitigates phospho-TDP-43 pathology and rescues TDP-43-induced impairments in synaptic integrity and long-term synaptic plasticity. In isolated mitochondria, the S59L mutation induces the aggregation of resident CHCHD10
protein as well as the aggregation and slower turnover of recombinant TDP-43 imported into mitochondria. Likewise, in an in vitro cell-free system, the S59L mutation induces the aggregation of CHCHD10
protein while simultaneously enhancing the aggregation of recombinant TDP-43, as evidenced by filter trap assays and atomic force microscopy. In contrast, recombinant CHCHD10
inhibits the growth of TDP-43 aggregates. These results in human brains, transgenic mice, and in vitro systems substantiate the role of wild type and mutant CHCHD10 in modulating mitochondrial CHCHD10 and TDP-43 pathogenesis together with associated phenotypes in long-term synaptic plasticity and motor unit physiology in mice and humans.