Neuronal Store-Operated Calcium Entry Pathway as a Novel Therapeutic Target for Huntington's Disease Treatment

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• 作者：Jun Wu¹ ; ⁴ ; Hsin-Pei Shih² ; ⁴ ; ⁵ ; Vladimir Vigont³ ; ⁴ ; Lori Hrdlicka² ; Len Diggins² ; Carol Singh² ; Matt Mahoney² ; Richard Chesworth² ; Gideon Shapiro² ; Olga Zimina³ ; Xuesong Chen¹ ; Qingqing Wu¹ ; Lyubov Glushankova³ ; Michael Ahlijanian² ; ⁶ ; Gerhard Koenig² ; Galina  ; N. Mozhayeva³ ; Elena Kaznacheyeva³ ; Ilya Bezprozvanny¹ ; ^{Ilya.Bezprozvanny@UTSouthwestern.edu"" rel=""nofollow}
• 刊名：Chemistry & Biology
• 出版年：2011
• 出版时间：24 June 2011
• 年：2011
• 卷：18
• 期：6
• 页码：777-793
• 全文大小：2493 K

文摘

Summary

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 (Ca²⁺) 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.