Referenced in: none

Automatically associated channels: TRP , TRPC , TRPC1

Title: Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment.

Authors: Jun Wu, Hsin-Pei Shih, Vladimir Vigont, Lori Hrdlicka, Len Diggins, Carol Singh, Matt Mahoney, Richard Chesworth, Gideon Shapiro, Olga Zimina, Xuesong Chen, Qingqing Wu, Lyubov Glushankova, Michael Ahlijanian, Gerhard Koenig, Galina N Mozhayeva, Elena Kaznacheyeva, Ilya Bezprozvanny

Journal, date & volume: Chem. Biol., 2011 Jun 24 , 18, 777-93

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21700213

Abstract
Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion within Huntingtin (Htt) protein. In the phenotypic screen we identified a class of quinazoline-derived compounds that delayed a progression of a motor phenotype in transgenic Drosophila HD flies. We found that the store-operated calcium (Ca(2+)) entry (SOC) pathway activity is enhanced in neuronal cells expressing mutant Htt and that the identified compounds inhibit SOC pathway in HD neurons. The same compounds exerted neuroprotective effects in glutamate-toxicity assays with YAC128 medium spiny neurons primary cultures. We demonstrated a key role of TRPC1 channels in supporting SOC pathway in HD neurons. We concluded that the TRPC1-mediated neuronal SOC pathway constitutes a novel target for HD treatment and that the identified compounds represent a novel class of therapeutic agents for treatment of HD and possibly other neurodegenerative disorders.