Huntington’s disease (HD) is a hereditary neurodegenerative disorder of the basal ganglia for which disease-modifying treatments are not yet available. Although gene-silencing therapies are currently being tested, further molecular mechanisms must be explored to identify druggable targets for HD. Cytoplasmic polyadenylation element binding proteins 1 to 4 (CPEB1 to CPEB4) are RNA binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Here, we found increased CPEB1 and decreased CPEB4 protein in the striatum of patients and mouse models with HD. This correlated with a reprogramming of polyadenylation in 17.3% of the transcriptome, markedly affecting neurodegeneration-associated genes including PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS, and HTT and suggesting a new molecular mechanism in neurodegenerative disease etiology. We found decreased protein content of top deadenylated transcripts, including striatal atrophy–linked genes not previously related to HD, such as KTN1 and the easily druggable SLC19A3 (the ThTr2 thiamine transporter). Mutations in SLC19A3 cause biotin-thiamine–responsive basal ganglia disease (BTBGD), a striatal disorder that can be treated with a combination of biotin and thiamine. Similar to patients with BTBGD, patients with HD demonstrated decreased thiamine in the cerebrospinal fluid. Furthermore, patients and mice with HD showed decreased striatal concentrations of thiamine pyrophosphate (TPP), the metabolically active form of thiamine. High-dose biotin and thiamine treatment prevented TPP deficiency in HD mice and attenuated the radiological, neuropathological, and motor HD-like phenotypes, revealing an easily implementable therapy that might benefit patients with HD.

中文翻译：

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CPEB 改变和异常转录组多腺苷酸化导致亨廷顿病中可治疗的 SLC19A3 缺陷

亨廷顿病 (HD) 是一种遗传性基底节神经退行性疾病，尚无改善疾病的治疗方法。尽管目前正在测试基因沉默疗法，但必须探索进一步的分子机制来确定 HD 的药物靶点。细胞质多聚腺苷酸化元件结合蛋白 1 至 4（CPEB1 至 CPEB4）是 RNA 结合蛋白，可通过缩短或延长其 poly(A) 尾来抑制或激活含有 CPE 的转录物的翻译。在这里，我们发现 HD 患者和小鼠模型的纹状体中 CPEB1 蛋白增加而 CPEB4 蛋白减少。这与 17.3% 转录组的多聚腺苷酸重编程相关，显着影响神经退行性变相关基因，包括PSEN1、MAPT、SNCA、LRRK2、PINK1、DJ1、SOD1、TARDBP、FUS和HTT，并提示了神经退行性疾病病因学中的新分子机制。我们发现顶部去腺苷酸化转录物的蛋白质含量降低，包括以前与 HD 不相关的纹状体萎缩相关基因，如KTN1和易于成药的SLC19A3（ThTr2 硫胺素转运蛋白）。SLC19A3中的突变引起生物素-硫胺素反应性基底神经节疾病 (BTBGD)，这是一种可以用生物素和硫胺素联合治疗的纹状体疾病。与 BTBGD 患者相似，HD 患者的脑脊液中硫胺素降低。此外，患有 HD 的患者和小鼠的纹状体浓度降低，焦磷酸硫胺素 (TPP) 是硫胺素的代谢活性形式。高剂量生物素和硫胺素治疗可预防 HD 小鼠的 TPP 缺乏症，并减弱放射学、神经病理学和运动 HD 样表型，揭示一种可能使 HD 患者受益的易于实施的治疗。