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Huntington's disease brain-derived small RNAs recapitulate associated neuropathology in mice.
Creus-Muncunill, Jordi; Guisado-Corcoll, Anna; Venturi, Veronica; Pantano, Lorena; Escaramís, Georgia; García de Herreros, Marta; Solaguren-Beascoa, Maria; Gámez-Valero, Ana; Navarrete, Cristina; Masana, Mercè; Llorens, Franc; Diaz-Lucena, Daniela; Pérez-Navarro, Esther; Martí, Eulàlia.
Afiliación
  • Creus-Muncunill J; Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Casanova 143, Barcelona, Catalonia, Spain.
  • Guisado-Corcoll A; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.
  • Venturi V; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain.
  • Pantano L; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • Escaramís G; Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Casanova 143, Barcelona, Catalonia, Spain.
  • García de Herreros M; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.
  • Solaguren-Beascoa M; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain.
  • Gámez-Valero A; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, Barcelona, Catalonia, Spain.
  • Navarrete C; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Masana M; Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Casanova 143, Barcelona, Catalonia, Spain.
  • Llorens F; Centro de Investigación Biomédica en Red sobre Epidemiología y Salud Pública (CIBERESP), Barcelona, Catalonia, Spain.
  • Diaz-Lucena D; Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Casanova 143, Barcelona, Catalonia, Spain.
  • Pérez-Navarro E; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.
  • Martí E; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain.
Acta Neuropathol ; 141(4): 565-584, 2021 04.
Article en En | MEDLINE | ID: mdl-33547932
Progressive motor alterations and selective death of striatal medium spiny neurons (MSNs) are key pathological hallmarks of Huntington's disease (HD), a neurodegenerative condition caused by a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene. Most research has focused on the pathogenic effects of the resultant protein product(s); however, growing evidence indicates that expanded CAG repeats within mutant HTT mRNA and derived small CAG repeat RNAs (sCAG) participate in HD pathophysiology. The individual contribution of protein versus RNA toxicity to HD pathophysiology remains largely uncharacterized and the role of other classes of small RNAs (sRNA) that are strongly perturbed in HD is uncertain. Here, we demonstrate that sRNA produced in the putamen of HD patients (HD-sRNA-PT) are sufficient to induce HD pathology in vivo. Mice injected with HD-sRNA-PT show motor abnormalities, decreased levels of striatal HD-related proteins, disruption of the indirect pathway, and strong transcriptional abnormalities, paralleling human HD pathology. Importantly, we show that the specific blockage of sCAG mitigates HD-sRNA-PT neurotoxicity only to a limited extent. This observation prompted us to identify other sRNA species enriched in HD putamen with neurotoxic potential. We detected high levels of tRNA fragments (tRFs) in HD putamen, and we validated the neurotoxic potential of an Alanine derived tRF in vitro. These results highlight that HD-sRNA-PT are neurotoxic, and suggest that multiple sRNA species contribute to striatal dysfunction and general transcriptomic changes, favoring therapeutic strategies based on the blockage of sRNA-mediated toxicity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Enfermedad de Huntington / ARN Pequeño no Traducido Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Acta Neuropathol Año: 2021 Tipo del documento: Article País de afiliación: España Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Enfermedad de Huntington / ARN Pequeño no Traducido Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Acta Neuropathol Año: 2021 Tipo del documento: Article País de afiliación: España Pais de publicación: Alemania