Wu J, Shih HP, Vigont V, Hrdlicka L, Diggins L, Singh C, Mahoney M, Chesworth R, Shapiro G, Zimina O, Chen X, Wu Q, Glushankova L, Ahlijanian M, Koenig G, Mozhayeva GN, Kaznacheyeva E, Bezprozvanny I.
Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment.
Chem Biol. 2011 Jun 24;18(6):777-93.
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This is a fascinating piece of translational work that provides a new line of support for the hypothesis that an alteration in calcium homeostasis is important in HD pathogenesis. The identification of a new small molecule that protects striatal neurons expressing mutant huntingtin is a key step toward the development of a viable neuroprotective strategy for this devastating disease. One of the most interesting aspects of the study is the suggestion that the expression of mutant huntingtin leads to the upregulation of a protein that enhances calcium entry into intracellular stores, but that normally plays little or no role in this process (the compounds identified in the fly screen had little or no effect in wild-type neurons). In the event that the quinazoline-derived compounds are not suitable for use in humans, the identification of the protein they target could be extremely valuable in developing alternative strategies for neuroprotection.
The study also provides a beautiful model of how to conduct unbiased translational studies for neurological diseases.