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
{"title":"I03 CPEB alteration and aberrant transcriptome-polyadenylation unveil a treatable vitamin B1 deficiency in huntington’s disease","authors":"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","doi":"10.1136/jnnp-2021-ehdn.117","DOIUrl":null,"url":null,"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.","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"8 1","pages":"0"},"PeriodicalIF":0.0000,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"I: Experimental therapeutics – preclinical","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1136/jnnp-2021-ehdn.117","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
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.