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I03 CPEB alteration and aberrant transcriptome-polyadenylation unveil a treatable vitamin B1 deficiency in huntington’s disease
  1. Sara Pico1,2,
  2. Alberto Parras1,2,
  3. María Santos-Galindo1,2,
  4. Julia Pose-Utrilla2,3,
  5. Margarita Castro1,4,5,
  6. Enrique Fraga1,2,
  7. Ivó H Hernández1,2,6,
  8. Ainara Elorza1,2,
  9. Héctor Anta7,8,
  10. Nan Wang9,
  11. Laura Martí-Sánchez5,10,
  12. Eulàlia Belloc8,
  13. Paula Garcia-Esparcia2,11,
  14. Juan J Garrido2,12,
  15. Isidro Ferrer2,11,
  16. Daniel Macías-García2,13,
  17. Pablo Mir2,13,
  18. Rafael Artuch5,10,
  19. Belén Pérez1,4,5,
  20. Félix Hernández1,2,
  21. Pilar Navarro7,14,15,
  22. José Luis López-Sendón16,
  23. Teresa Iglesias2,3,
  24. X William Yang9,
  25. Raúl Méndez8,17,
  26. José J Lucas1,2
  1. 1Center for Molecular Biology ‘Severo Ochoa’ (CBMSO) CSIC/UAM, Madrid, Spain
  2. 2Networking Research Center on Neurodegenerative Diseases (CIBERNED). Instituto de Salud Carlos III, Madrid, Spain
  3. 3Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain
  4. 4Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Madrid, Spain
  5. 5Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain
  6. 6Facultad de Ciencias, Departamento de Biología (Unidad Docente Fisiología Animal), Universidad Autónoma de Madrid, Madrid, Spain
  7. 7Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada I+D+i IMIM- IIBB (CSIC), Barcelona, Spain
  8. 8Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology, Barcelona, Spain
  9. 9Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
  10. 10Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
  11. 11Institute of Neuropathology; IDIBELL-University Hospital Bellvitge; University of Barcelona; Hospitalet de Llobregat; Barcelona, Spain
  12. 12Department of Molecular, Cellular and Developmental Neurobiology, Instituto Cajal (CSIC), Madrid, Spain
  13. 13Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
  14. 14Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, Spain
  15. 15 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  16. 16Department of Neurology, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
  17. 17Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain


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.

  • huntington’s disease
  • CPEB
  • RNA-binding proteins
  • poly(A)
  • polyadenylation
  • SLC19A3
  • thiamine deficiency
  • vitamin B1
  • biotin
  • therapy
  • preclinical testing

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