Small-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington’s disease
| Autor: | Anniefer N. Magpusao, Xiaoyan Sun, Di Hu, Drew J. Adams, Kathleen C. Lundberg, Benlian Wang, Xin Qi, Matthew A. Thompson, Yuriy Fedorov |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Dynamins
Male Proteasome Endopeptidase Complex Pyridines Science Primary Cell Culture General Physics and Astronomy Neuropathology Biology Molecular neuroscience Neuroprotection General Biochemistry Genetics and Molecular Biology Article Mice Huntington's disease GSK-3 medicine Animals Humans Calpastatin Neurons Multidisciplinary Glycogen Synthase Kinase 3 beta Effector Calpain Calcium-Binding Proteins High-throughput screening General Chemistry medicine.disease Corpus Striatum Cell biology Mitochondria Disease Models Animal Huntington Disease Neuroprotective Agents Pyrimidines Gene Expression Regulation Proteolysis biology.protein Signal transduction Injections Intraperitoneal Signal Transduction |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-19 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Mitochondrial dysfunction is a common hallmark of neurological disorders, and reducing mitochondrial damage is considered a promising neuroprotective therapeutic strategy. Here, we used high-throughput small molecule screening to identify CHIR99021 as a potent enhancer of mitochondrial function. CHIR99021 improved mitochondrial phenotypes and enhanced cell viability in several models of Huntington’s disease (HD), a fatal inherited neurodegenerative disorder. Notably, CHIR99201 treatment reduced HD-associated neuropathology and behavioral defects in HD mice and improved mitochondrial function and cell survival in HD patient-derived neurons. Independent of its known inhibitory activity against glycogen synthase kinase 3 (GSK3), CHIR99021 treatment in HD models suppressed the proteasomal degradation of calpastatin (CAST), and subsequently inhibited calpain activation, a well-established effector of neural death, and Drp1, a driver of mitochondrial fragmentation. Our results established CAST-Drp1 as a druggable signaling axis in HD pathogenesis and highlighted CHIR99021 as a mitochondrial function enhancer and a potential lead for developing HD therapies. Mitochondrial dysfunction is a common hallmark of neurological disorders. Here, the authors identify CHIR99021 as a potent enhancer of mitochondrial function, which improved mitochondrial phenotypes in Huntington’s disease models. CHIR99021 was shown to stabilize calpastatin, which suppressed calpain activation and Drp1-induced mitochondrial fragmentation. |
| Databáze: | OpenAIRE |
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