CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington's disease.

Autor:	Picó S; Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain., Parras A; Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain., Santos-Galindo M; Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain., Pose-Utrilla J; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain.; Instituto de Investigaciones Biomédicas 'Alberto Sols,' Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid 28029, Spain., Castro M; Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain.; Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Madrid 28049, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid,28029, Spain., Fraga E; Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain., Hernández IH; Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain.; Facultad de Ciencias, Departamento de Biología (Unidad Docente Fisiología Animal), Universidad Autónoma de Madrid, Madrid 28049, Spain., Elorza A; Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain., Anta H; Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada I+D+i IMIM-IIBB (CSIC), Barcelona 08003, Spain.; Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology, Barcelona 08028, Spain., Wang N; Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA., Martí-Sánchez L; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid,28029, Spain.; Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Barcelona 08950, Spain., Belloc E; Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology, Barcelona 08028, Spain., Garcia-Esparcia P; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain.; Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Hospitalet de Llobregat, Barcelona 08908, Spain., Garrido JJ; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain.; Department of Molecular, Cellular, and Developmental Neurobiology, Instituto Cajal (CSIC), Madrid 28002, Spain., Ferrer I; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain.; Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Hospitalet de Llobregat, Barcelona 08908, Spain., Macías-García D; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain.; Unidad 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 41013, Spain., Mir P; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain.; Unidad 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 41013, Spain., Artuch R; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid,28029, Spain.; Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Barcelona 08950, Spain., Pérez B; Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain.; Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Madrid 28049, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid,28029, Spain., Hernández F; Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain., Navarro P; Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada I+D+i IMIM-IIBB (CSIC), Barcelona 08003, Spain.; Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona 08036, Spain.; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain., López-Sendón JL; Department of Neurology, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid 28034, Spain., Iglesias T; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain.; Instituto de Investigaciones Biomédicas 'Alberto Sols,' Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid 28029, Spain., Yang XW; Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA., Méndez R; Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology, Barcelona 08028, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain., Lucas JJ; Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, 28031, Spain.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2021 Sep 29; Vol. 13 (613), pp. eabe7104. Date of Electronic Publication: 2021 Sep 29.
DOI:	10.1126/scitranslmed.abe7104
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu