Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology Warsaw, Poland.
Front Mol Neurosci. 2013 Nov 25;6:42. doi: 10.3389/fnmol.2013.00042. eCollection 2013.
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 Ca(2+) 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.
亨廷顿病（HD）是一种遗传性神经退行性疾病，由亨廷顿（HTT）蛋白中多聚谷氨酰胺延伸引起，并以钙稳态失调为特征。我们研究了这些紊乱是否与编码钙稳态和信号转导相关蛋白的基因（即钙小体）的 mRNA 水平变化相关。使用包含 96 个基因探针的定制 TaqMan 低密度阵列，我们定量测定了 YAC128 小鼠（HD 模型）和野生型小鼠纹状体中的 mRNA。HTT 突变导致钙信号体的一些成分的表达增加，包括钙调蛋白、早老素 2 和钙调蛋白 1，以及间接参与钙稳态的基因的表达增加，如亨廷顿相关蛋白 1 和钙调蛋白结合蛋白。为了在另一个模型中验证这些发现，我们使用了具有可诱导表达突变全长 HTT 的 PC12 细胞。使用 Fura-2AM 的单细胞成像，我们发现由于突变 HTT 的表达，导致了储存操作的 Ca（2+）内流而不是内质网（ER）储存含量的改变。在表达突变 HTT 的细胞中，检测到 Orai 钙通道亚基 2、钙调蛋白和 septin 4 的统计学显著下调。我们的数据表明，钙稳态的失调与钙小体成员的基因表达变化相关。然而，在本研究中使用的两种 HD 模型中，这些变化有所不同。我们的结果表明，每个 HD 模型都表现出独特的特征，这些特征可能仅部分类似于人类疾病。
