Departments of Molecular Biophysics, Bogomoletz Institute of Physiology, Kyiv, Ukraine; Kyiv Academic University, Ukraine.
Departments of Molecular Biophysics, Bogomoletz Institute of Physiology, Kyiv, Ukraine.
Neurobiol Dis. 2019 Dec;132:104529. doi: 10.1016/j.nbd.2019.104529. Epub 2019 Jul 10.
A recent report of autosomal-recessive primary isolated dystonia (DYT2 dystonia) identified mutations in HPCA, a gene encoding a neuronal calcium sensor protein, hippocalcin (HPCA), as the cause of this disease. However, how mutant HPCA leads to neuronal dysfunction remains unknown. Using a multidisciplinary approach, we demonstrated the failure of dystonic N75K HPCA mutant to decode short bursts of action potentials and theta rhythms in hippocampal neurons by its Ca-dependent translocation to the plasma membrane. This translocation suppresses neuronal activity via slow afterhyperpolarization (sAHP) and we found that the N75K mutant could not control sAHP during physiologically relevant neuronal activation. Simulations based on the obtained experimental results directly demonstrated an increased excitability in neurons expressing N75K mutant instead of wild type (WT) HPCA. In conclusion, our study identifies sAHP as a downstream cellular target perturbed by N75K mutation in DYT2 dystonia, demonstrates its impact on neuronal excitability, and suggests a potential therapeutic strategy to efficiently treat DYT2.
最近的一份常染色体隐性原发性孤立性肌张力障碍（DYT2 型肌张力障碍）报告确定了 HPCA 基因突变是导致这种疾病的原因，HPCA 是一种编码神经元钙传感器蛋白——海普卡因（HPCA）的基因。然而，突变的 HPCA 如何导致神经元功能障碍仍然未知。我们采用多学科方法，证明了 N75K 突变型张力障碍 HPCA 不能通过其钙依赖性易位到质膜来解码海马神经元的短爆发动作电位和θ节律。这种易位通过缓慢后超极化（sAHP）抑制神经元活性，我们发现 N75K 突变体在生理相关的神经元激活期间无法控制 sAHP。基于获得的实验结果的模拟直接证明了表达 N75K 突变体而非野生型（WT）HPCA 的神经元兴奋性增加。总之，我们的研究确定 sAHP 是 DYT2 型肌张力障碍中 N75K 突变干扰的下游细胞靶点，证明了它对神经元兴奋性的影响，并提出了一种有效治疗 DYT2 的潜在治疗策略。
