I03 CPEB alteration and aberrant transcriptome-polyadenylation unveil a treatable vitamin B1 deficiency in huntington’s disease

S. Picó, A. Parras, M. Santos-Galindo, Julia Pose-Utrilla, M. Castro, Enrique Fraga, Ivó H Hernández, Ainara Elorza, Héctor Anta, Nan Wang, L. Martí-Sánchez, Eulàlia Belloc, Paula Garcia-Esparcia, J. J. Garrido, I. Ferrer, D. Macías-García, P. Mir, R. Artuch, Belén Pérez, F. Hernández, P. Navarro, J. López-Sendón, T. Iglesias, X. W. Yang, Raúl Méndez, J. Lucas
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Abstract

Background Although promising gene-silencing therapies are being tested for Huntington’s disease (HD), no disease-modifying treatments are available. Thus, study of molecular mechanisms underneath Htt-mutation must continue to identify easily druggable targets. Cytoplasmic polyadenylation element binding proteins 1–4 (CPEB1–4) are RNA-binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Alteration of CPEB-dependent transcriptome polyadenylation has been associated to diseases like cancer, autism and epilepsy. Aims Analyze CPEBs and polyadenylation in HD. Identify easily druggable targets among genes mis-expressed due to altered CPEB-dependent polyadenylation, to assay them in HD mice. Methods a) Western blot and immunostaining of CPEBs in brains of HD patients and mouse models. b) Genome-wide poly(A)-tail analysis through poly(U) chromatography+gene chip. c) status of CPEB targets and related metabolites by western blot and HPLC. d) radiological, neuropathological and behavioural analysis of HD mice receiving target-related treatment. Results There is a CPEB1/4 imbalance in HD striatum with concomitant altered transcriptome polyadenylation affecting many neurodegeneration-linked genes like PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS and HTT. Among top deadenylated genes was SLC19A3 (ThTr2 thiamine transporter) whose mutation causes biotin+thiamine responsive basal ganglia disease (BTBGD). Decreased ThTr2 in HD and HD mice led us to discover that HD is in part a BTBG-like thiamine deficiency. Remarkably, high dose biotin+thiamine treatment prevented the thiamine deficiency of HD mice and attenuated their radiological, neuropathological and motor phenotypes. Conclusions This study unveils altered polyadenylation as a new molecular mechanism in neurodegeneration uncovering HD as a thiamine deficiency and, therefore, an easy to implement therapy.
CPEB改变和异常转录组聚腺苷化揭示了亨廷顿病可治疗的维生素B1缺乏症
虽然有希望的基因沉默疗法正在测试亨廷顿舞蹈病(HD),没有疾病修饰治疗可用。因此,对http突变分子机制的研究必须继续确定易于药物治疗的靶点。胞质聚腺苷化元件结合蛋白1-4 (CPEB1-4)是一种rna结合蛋白,通过缩短或延长含有cpe的转录本的聚(A)尾来抑制或激活其翻译。cpeb依赖性转录组多腺苷化的改变与癌症、自闭症和癫痫等疾病有关。目的分析HD患者的cpeb与聚腺苷化关系。在由于cpeb依赖性聚腺苷酸化改变而错误表达的基因中确定容易药物靶标,并在HD小鼠中进行检测。方法a) HD患者和小鼠模型脑cpeb的Western blot和免疫染色。b)全基因组poly(A)- poly(U)色谱+基因芯片尾部分析。c) western blot和HPLC检测CPEB靶点及相关代谢物的状态。d)接受靶向相关治疗的HD小鼠放射学、神经病理学和行为分析。结果HD纹状体存在CPEB1/4失衡,并伴有转录组多腺苷化改变,影响PSEN1、MAPT、SNCA、LRRK2、PINK1、DJ1、SOD1、TARDBP、FUS和HTT等神经变性相关基因。SLC19A3 (ThTr2硫胺素转运蛋白)是死基化程度最高的基因之一,其突变可导致生物素+硫胺素反应性基底神经节病(BTBGD)。在HD和HD小鼠中ThTr2的减少使我们发现HD部分是btbg样硫胺素缺乏症。值得注意的是,高剂量生物素+硫胺素治疗可以预防HD小鼠的硫胺素缺乏症,并减轻其放射学、神经病理学和运动表型。本研究揭示了改变的聚腺苷酸化是神经退行性疾病的一种新的分子机制,揭示了HD是一种硫胺素缺乏症,因此是一种易于实施的治疗方法。
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