ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response
| Autor: | Samantha Meadows, Crystal Davis, Suzanne R. Burstein, Corey Anderson, Aamir Zuberi, Kirsten Bredvik, Teresa A. Milner, Jalia Dash, Alessandra Piersigilli, Giovanni Manfredi, Cathleen M. Lutz, Hibiki Kawamata, Laure Case |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Respiratory chain Mice Transgenic Biology medicine.disease_cause Article Pathology and Forensic Medicine 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Downregulation and upregulation Mitochondrial myopathy Gene knockin medicine Integrated stress response Animals Myopathy Genetic Association Studies Mutation Neurodegeneration Parkinson Disease medicine.disease Cell biology Mitochondria 030104 developmental biology Frontotemporal Dementia Gain of Function Mutation Mitochondrial Membranes Neurology (clinical) medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Acta Neuropathol |
| Popis: | Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice harboring the mouse-equivalent of a disease associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10(S55L) mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10(S55L) mice, leading to aberrant organelle morphology and function. Aggregates induce a potent mitochondrial integrated stress response (mtISR) through mTORC1 activation, with elevation of stress-induced transcription factors, secretion of myokines, upregulated serine and one-carbon metabolism, and downregulation of respiratory chain enzymes. Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10(S55L)-dependent disease pathology is not caused by loss-of-function. Overall, CHCHD10(S55L) mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation. |
| Databáze: | OpenAIRE |
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