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 which delayed a progression of a motor phenotype in transgenic Drosophila HD flies. We found that the storeoperated 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 MSN 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.

Store-Operated Calcium Entry through Orai Is Required for Transcriptional Maturation of the Flight Circuit inDrosophila

“…These observations support the idea that in Drosophila neurons, Ca 2ϩ release from ER stores through the IP 3 R triggers SOCE through STIM and Orai (Venkiteswaran and Hasan, 2009). A similar signaling mechanism exists in mammalian Purkinje neurons (Wu et al, 2011;Hartmann et al, 2014). Here we investigated the spatiotemporal requirement of SOCE for flight in Drosophila neurons and have identified a requirement for SOCE in dopaminergic neurons during pupal development.…”

Experimental Models for Identifying Modifiers of Polyglutamine-Induced Aggregation and Neurodegeneration

“…Analogously, a Drosophila HD model in which panneuronal expression of mHTT resulted in a motor phenotypic impairment (limb tremors and climbing) was used in a screen of 521 quinazoline-derived compounds that identified compound EVP4593 as a potent suppressor of the climbing defect [81]. In secondary assays, EVP4593 was also shown able to protect cultured primary medium spiny neurons (MSNs) isolated from transgenic HD mice (YAC128) from glutamate-induced toxicity.…”

Drosophila melanogaster: A Promising System for Neurobiology Research

“…Indeed, Drosophila disease models have been used comprehensively to generate significant information regarding disease pathogenicity, identification of novel genetic modifiers and chemical compounds [26][27][28]. A large number of genetic modifiers have already been identified in case of Huntington's disease alone, which could be categorized in several sub-groups as per their functional characteristics [6,9].…”