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MINI-REVIEW: Normalization of Calcium Balance in Striatal Neurons in Huntington’s Disease: Sigma 1 Receptor as a Potential Target for Therapy

Nina A. Kraskovskaya1,a* and Ilya B. Bezprozvanny1,2,b

1Laboratory of Molecular Neurodegeneration, Peter the Great Saint-Petersburg Polytechnic University, 195251 Saint-Petersburg, Russia

2Department of Physiology, UT Southwestern Medical Center at Dallas, 75390 Dallas, USA

* To whom correspondence should be addressed.

Received October 16, 2020; Revised December 24, 2020; Accepted December 24, 2020
Huntington’s disease (HD) is a neurodegenerative, dominantly inherited genetic disease caused by expansion of the polyglutamine tract in the huntingtin gene. At the cellular level, HD is characterized by the accumulation of mutant huntingtin protein in brain cells, resulting in the development of the HD phenotype, which includes mental disorders, decreased cognitive abilities, and progressive motor impairments in the form of chorea. Despite numerous studies, no unambigous connection between the accumulation of mutant protein and selective death of striatal neurons has yet been established. Recent studies have shown impairments in the calcium homeostasis in striatal neurons in HD. These cells are extremely sensitive to changes in the cytoplasmic concentration of calcium and its excessive increase leads to their death. One of the possible ways to normalize the balance of calcium in striatal neurons is through the sigma 1 receptor (S1R), which act as a calcium sensor that also exhibits modulating chaperone activity upon the cell stress observed during the development of many neurodegenerative diseases. The fact that S1R is a ligand-operated protein makes it a new promising molecular target for the development of drug therapy of HD based on the agonists of this receptor.
KEY WORDS: sigma 1 receptor, Huntington’s disease, dendritic spines, Ca2+, store-operated calcium entry, endoplasmic reticulum

DOI: 10.1134/S0006297921040076