title: Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment.
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.
authors.affiliation: Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Hsin-Pei
authors.initials: HP
authors.lastname: Shih
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vigont
authors.forename: Lori
authors.initials: L
authors.lastname: Hrdlicka
authors.forename: Len
authors.initials: L
authors.lastname: Diggins
authors.forename: Carol
authors.initials: C
authors.lastname: Singh
authors.forename: Matt
authors.initials: M
authors.lastname: Mahoney
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
authors.forename: Gideon
authors.initials: G
authors.lastname: Shapiro
authors.forename: Olga
authors.initials: O
authors.lastname: Zimina
authors.forename: Xuesong
authors.initials: X
authors.lastname: Chen
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wu
authors.forename: Lyubov
authors.initials: L
authors.lastname: Glushankova
authors.forename: Michael
authors.initials: M
authors.lastname: Ahlijanian
authors.forename: Gerhard
authors.initials: G
authors.lastname: Koenig
authors.forename: Galina N
authors.initials: GN
authors.lastname: Mozhayeva
authors.forename: Elena
authors.initials: E
authors.lastname: Kaznacheyeva
authors.forename: Ilya
authors.initials: I
authors.lastname: Bezprozvanny
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004330:Drosophila; D016257:Fura-2 / Q000737:chemistry; D018698:Glutamic Acid / Q000494:pharmacology; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010647:Phenyl Ethers / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C562064:EVP 4593; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010647:Phenyl Ethers; D011799:Quinazolines; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D018698:Glutamic Acid; D002118:Calcium; D016257:Fura-2