Abstract
Huntington's disease (HD) is a hereditary neurodegenerative disease caused by the expansion of a polyglutamine stretch in the huntingtin (HTT) protein and characterized by dysregulated calcium homeostasis. We investigated whether these disturbances are correlated with changes in the mRNA level of the genes that encode proteins involved in calcium homeostasis and signaling (i.e., the calciosome). Using custom-made TaqMan low-density arrays containing probes for 96 genes, we quantified mRNA in the striatum in YAC128 mice, a model of HD, and wildtype mice. HTT mutation caused the increased expression of some components of the calcium signalosome, including calretinin, presenilin 2, and calmyrin 1, and the increased expression of genes indirectly involved in calcium homeostasis, such as huntingtin-associated protein 1 and calcyclin-binding protein. To verify these findings in a different model, we used PC12 cells with an inducible expression of mutated full-length HTT. Using single-cell imaging with Fura-2AM, we found that store-operated Ca2+ entry but not endoplasmic reticulum (ER) store content was changed as a result of the expression of mutant HTT. Statistically significant downregulation of the Orai calcium channel subunit 2, calmodulin, and septin 4 was detected in cells that expressed mutated HTT. Our data indicate that the dysregulation of calcium homeostasis correlates with changes in the gene expression of members of the calciosome. These changes, however, differed in the two models of HD used in this study. Our results indicate that each HD model exhibits distinct features that may only partially resemble the human disease.
Highlights
Cellular calcium transients control a vast array of cellular functions, from short-term responses to the long-term regulation of cell growth and proliferation
To estimate the relative mRNA levels of the ensemble of genes that encode the calciosome, custom-made RT-qPCR arrays were prepared containing genes expressed in the mouse brain according to the Allen Brain Atlas
We dissected the striatum from 3-month-old YAC128 mice and non-transgenic controls and analyzed the expression of four standards, 57 calciosome genes, as well as genes implicated in Huntington’s disease (HD) and Alzheimer’s disease (AD) using two technical replicates
Summary
Cellular calcium transients control a vast array of cellular functions, from short-term responses (e.g., contraction and secretion) to the long-term regulation of cell growth and proliferation. IP3 interacts with its receptors (IP3R1-3) on the membrane of the endoplasmic reticulum (ER), the major store of Ca2+ in the cell The opening of these IP3R Ca2+ channels releases Ca2+ stored in the ER (Foskett et al, 2007). The depletion of ER Ca2+ stores results in activation of store-operated channels (SOCs) at the plasma membrane, mediating store-operated calcium entry (SOCE) from the extracellular space, followed by the removal of cytosolic Ca2+ and replenishment of luminal Ca2+ through sarcoplasmic/ER Ca2+-adenosine triphosphatases (ATPases; SERCA1-3). Considering their electrophysiological and molecular properties, two main types of SOCs can be described
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