chir-99021 and Huntington-Disease

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.

Topics: Animals; Calcium-Binding Proteins; Calpain; Corpus Striatum; Disease Models, Animal; Dynamins; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta; Humans; Huntington Disease; Injections, Intraperitoneal; Male; Mice; Mitochondria; Neurons; Neuroprotective Agents; Primary Cell Culture; Proteasome Endopeptidase Complex; Proteolysis; Pyridines; Pyrimidines; Signal Transduction