Small-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington’s disease
Year: 2021
Type: article
Abstract: 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.
Source: Nature Communications
Authors: Di Hu, Xiaoyan Sun, Anniefer Magpusao, Yuriy Fedorov, Matthew Thompson, Benlian Wang, Kathleen Lundberg, Drew J. Adams, Xin Qi
Institution: Case Western Reserve University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,560
Funders: U.S. Department of Health and Human Services, Case Western Reserve University, Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Case Western Reserve University, Dr. Ralph and Marian Falk Medical Research Trust, Broad Institute, Mt. Sinai Health Care Foundation, National Institutes of Health, National Institute on Aging, National Eye Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Awards: G1273157147, G136488028, G2251073972, Q Exactive HF-X hybrid quadrupole-Orbitrap mass spectrometer (QE HF-X), Role of brain lipid metabolism in Alzheimer's disease, G3718339214, Mitochondrial biomarkers in Huntington's disease, G5822270753, G6194814182, Proteostasis dysregulation and alpha-synuclein, G9000202443, Case Comprehensive Cancer Center Support Grant, CWRU NEI Vision Center Core Grant
OpenAlex ID: W3197820799