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Published on: January 22, 2017
A small-molecule stabilizer of the calpastatin-calpain-2 complex restores mitochondrial function and mitigates
Di Hu1,2, Xiaoyan Sun1, Yutong Shang1
1Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Abstract:
Mitochondrial dysfunction and dysregulated proteolysis drive Huntington's disease (HD), tauopathy, and related neurodegenerative disorders. Calpain-2, a Ca2+-activated protease restrained by calpastatin (CAST), is pathologically overactivated, yet no therapies directly target this axis. We identify A36, a brain-penetrant small molecule derived from CHIR99021 that selectively stabilizes the CAST-calpain-2 complex without inhibiting GSK3. A36 acts as a protein-protein interaction stabilizer, enhancing CAST-calpain-2 binding, preventing CAST degradation, and thereby limiting calpain-2 activation and mitochondrial damage. In patients with HD induced pluripotent stem cell-derived neurons and mutant mouse striatal neurons, A36 normalized mitochondrial morphology and membrane potential, reduced oxidative stress, and improved survival. In vivo, A36 displayed favorable pharmacokinetics and central nervous system exposure; treatment reduced striatal neurodegeneration, mutant huntingtin aggregation, and motor deficits in HD R6/2 mice, and lowered phosphorylated tau, neuroinflammation, and cognitive decline in tauopathy PS19 mice. These findings establish pharmacological stabilization of CAST-calpain-2 as a therapeutic strategy and position A36 as a mechanism-selective modulator with broad neurodegenerative disease potential.
Insights
A new drug, A36, stabilizes a key protein complex to protect against neurodegeneration in Huntington's disease and tauopathy models. This approach targets mitochondrial dysfunction and offers potential for treating related brain disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Mitochondrial dysfunction and abnormal protein breakdown are hallmarks of neurodegenerative diseases like Huntington's disease (HD) and tauopathy.
- Calpain-2, a calcium-activated protease, is often overactive in these conditions, but current therapies do not target this pathway.
Purpose of the Study:
- To identify and characterize a novel therapeutic agent that selectively modulates the calpastatin-calpain-2 (CAST-calpain-2) interaction to treat neurodegenerative disorders.
- To evaluate the efficacy of A36 in cellular and animal models of HD and tauopathy.
Main Methods:
- Developed A36, a small molecule that stabilizes the CAST-calpain-2 complex without affecting GSK3.
- Tested A36 in patient-derived induced pluripotent stem cells and mouse models of HD and tauopathy.
- Assessed mitochondrial function, oxidative stress, neurodegeneration, protein aggregation, neuroinflammation, and cognitive/motor deficits.
Main Results:
- A36 normalized mitochondrial function, reduced oxidative stress, and improved neuronal survival in HD models.
- In vivo, A36 demonstrated good brain penetration and reduced neurodegeneration, mutant huntingtin aggregation, and motor deficits in HD mice.
- A36 treatment also decreased phosphorylated tau, neuroinflammation, and cognitive decline in tauopathy mice.
Conclusions:
- Pharmacological stabilization of the CAST-calpain-2 complex is a viable therapeutic strategy for neurodegenerative diseases.
- A36 is a potent, mechanism-selective drug candidate with broad potential for treating conditions like Huntington's disease and tauopathy.
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