Journal
FRONTIERS IN PHYSIOLOGY
Volume 6, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2015.00337
Keywords
store-operated calcium entry; Huntington's disease; ionic channels; neurodegeneration; TRPC1; Orai1; STIM1
Categories
Funding
- Russian Science Foundation [14-14-00720]
- program Molecular and Cellular Biology of the Russian Academy of Sciences
- Scientific School Support: Program [SS-1721.2014.4]
- Russian Foundation for Basic Research [14-04-31137, 14-04-31611]
- President of the Russian Federation
- Russian Science Foundation [14-14-00720] Funding Source: Russian Science Foundation
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It has been previously reported that N-terminus of mutant huntingtin (product of the 1st exon) is sufficient to cause a Huntington's disease (HD) pathological phenotype. In view of recent data suggesting that improper regulation of store-operated calcium (SOC) channels is involved in neurodegenerative processes, we investigated influence of expression of the mutant huntingtin N-terminal fragment (Htt138Q-1exon) on SOC entry (SOCE) in mouse neuroblastoma cells (Neuro-2a) and in primary culture of medium spiny neurons (MSNs) isolated from mice. The results show that SOCE in these cells is enhanced upon lentiviral expression of the Htt138Q-1exon. Moreover, we demonstrated that RNAi-mediated knockdown of TRPC1, Orai1, or STIM1 proteins leads to dramatic reduction of abnormal SOCE in both Neuro-2a and MSNs, expressing Htt138Q-1 exon. Thus, we concluded that abnormal SOCE in these cells is maintained by both TRPC1- and Orai1-containing channels and required STIM1 for its activation. Furthermore, EVP4593 compound previously tested as a potential anti-HD drug in a Drosophila screening system has proved to be capable of reducing SOCE to the normal level in MSNs expressing the Htt1380-1exon.
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