Abstract
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-1exon. 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 Htt138Q-1exon.
Highlights
Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of CAG repeat in the gene encoding huntingtin, a protein of unknown function, with the consequent expansion of polyglutamine tract in this gene product
We have previously found that Store-operated calcium entry (SOCE) in SK-N-SH human neuroblastoma cells is enhanced due to the expression of full-length mutant huntingtin (Glushankova et al, 2010; Wu et al, 2011), whereas, according to Tang et al (2003), the expression of exon 1 of mutated huntingtin (Htt138Q-1exon) alone is sufficient for enhancing the affinity of IP3 receptor (IP3R) to IP3
Most of known effects of mutated huntingtin on calcium signaling involve an increase in the intracellular calcium level, which can lead to calcium overload of mitochondria, activation of caspases, and eventual cell death
Summary
Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of CAG repeat in the gene encoding huntingtin, a protein of unknown function, with the consequent expansion of polyglutamine tract in this gene product. In addition to HD, eight more inherited neurodegenerative diseases are known to be caused by polyglutamine expansion in the protein products of other genes, which form insoluble aggregates in neurons. It has been reported that some forms of huntingtin aggregation contribute to neuronal death (Bates, 2003; Arribat et al, 2013). The activity of SOC channels has been demonstrated both in nonexcitable cells (Parekh and Penner, 1997) and in neurons
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