Small-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington’s disease

Di Hu, Xiaoyan Sun, Anniefer Magpusao, Yuriy Fedorov, Matthew Thompson, Benlian Wang, Kathleen Lundberg, Drew J. Adams () and Xin Qi ()
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Di Hu: Case Western Reserve University School of Medicine
Xiaoyan Sun: Case Western Reserve University School of Medicine
Anniefer Magpusao: Case Western Reserve University School of Medicine
Yuriy Fedorov: Case Western Reserve University School of Medicine
Matthew Thompson: Case Western Reserve University School of Medicine
Benlian Wang: Case Western Reserve University School of Medicine
Kathleen Lundberg: Case Western Reserve University School of Medicine
Drew J. Adams: Case Western Reserve University School of Medicine
Xin Qi: Case Western Reserve University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25651-y

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