Department of Medical Genetics and Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada.
Aging Dis. 2023 Dec 1;14(6):2249-2266. doi: 10.14336/AD.2023.0423.
Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT in humans or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in approximately 28% of FVB/N mice, which we have called FVB/N Seizure Disorder with SUDEP (FSDS). These abnormal FVB/N mice demonstrate the cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, mice heterozygous for the targeted inactivation of Htt (Htt+/- mice) exhibit an increased frequency of this disorder (71% FSDS phenotype), while over-expression of either full length wild-type HTT in YAC18 mice or full length mutant HTT in YAC128 mice completely prevents it (0% FSDS phenotype). Examination of the mechanism underlying huntingtin's ability to modulate the frequency of this seizure disorder indicated that over-expression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by decreasing huntingtin levels have ramifications for huntingtin-lowering therapies that are being developed to treat HD.
亨廷顿病（HD）是一种成人发病的神经退行性疾病，由 HTT 基因中的三核苷酸 CAG 重复扩展引起，该基因编码 huntingtin（人类中的 HTT 或小鼠中的 Htt）蛋白。HTT 是一种多功能、广泛表达的蛋白质，对胚胎存活、正常神经发育和成年大脑功能至关重要。野生型 HTT 保护神经元免受各种形式的死亡的能力提出了这样一种可能性，即正常 HTT 功能的丧失可能会使 HD 中的疾病进展恶化。降低 HTT 的治疗方法正在 HD 的临床试验中进行评估，但人们担心降低野生型 HTT 水平可能会产生不良影响。在这里，我们表明 Htt 水平调节自发性发生在大约 28%的 FVB/N 小鼠中的特发性癫痫发作障碍的发生，我们将其称为 FVB/N 癫痫伴猝倒（FSDS）。这些异常的 FVB/N 小鼠表现出包括自发性癫痫发作、星形胶质细胞增生、神经元肥大、脑源性神经营养因子（BDNF）上调和与癫痫相关的突发性死亡在内的癫痫小鼠模型的主要特征。有趣的是，HTT 靶向失活的杂合子（Htt+/- 小鼠）表现出这种疾病的频率增加（71%FSDS 表型），而 YAC18 小鼠中全长野生型 HTT 的过表达或 YAC128 小鼠中全长突变 HTT 的过表达完全阻止它（0%FSDS 表型）。对 huntingtin 调节这种癫痫发作障碍频率的机制的研究表明，全长 HTT 的过表达可以促进癫痫发作后的神经元存活。总的来说，我们的结果表明 huntingtin 在这种形式的癫痫中具有保护作用，并为在青少年 HD、Lopes-Maciel-Rodan 综合征和 Wolf-Hirschhorn 综合征中观察到癫痫发作提供了合理的解释。降低 huntingtin 水平引起的不良反应对正在开发用于治疗 HD 的 huntingtin 降低疗法产生了影响。
