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Huntington’s disease brain-derived small RNAs recapitulate associated neuropathology in mice

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Abstract

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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Acknowledgements

This work was supported by the Spanish government through the Spanish Ministry of Economy and Competitiveness (MINECO) and the Fondo Europeo de Desarrollo Regional (FEDER) (Project SAF2017-88452-R to EM and PID2019-106447RB-100 to EPN). We acknowledge support of the Spanish Ministry of Science Innovation and Universities through the “Maria Maeztu Unit of Excellence Program”. We thank the staff of the Genomics Unit and the Bioinformatics unit at the CRG for RNA-seq performance and analysis, and A. López and M.T. Muñoz for their technical support. AGC is supported by a fellowship from the Fundación Tatiana Pérez de Guzmán el Bueno.

Author information

Author notes

  1. Jordi Creus-Muncunill

    Present address: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

  2. Jordi Creus-Muncunill and Anna Guisado-Corcoll have contributed equally to this work.

Authors and Affiliations

  1. Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Casanova 143, Barcelona, Catalonia, Spain

    Jordi Creus-Muncunill, Anna Guisado-Corcoll, Georgia Escaramís, Marta García de Herreros, Maria Solaguren-Beascoa, Ana Gámez-Valero, Mercè Masana, Esther Pérez-Navarro & Eulàlia Martí

  2. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain

    Jordi Creus-Muncunill, Anna Guisado-Corcoll, Marta García de Herreros, Mercè Masana & Esther Pérez-Navarro

  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain

    Jordi Creus-Muncunill, Anna Guisado-Corcoll, Marta García de Herreros, Mercè Masana, Franc Llorens, Daniela Diaz-Lucena & Esther Pérez-Navarro

  4. Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, Barcelona, Catalonia, Spain

    Veronica Venturi, Cristina Navarrete & Eulàlia Martí

  5. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Lorena Pantano

  6. Centro de Investigación Biomédica en Red sobre Epidemiología y Salud Pública (CIBERESP), Barcelona, Catalonia, Spain

    Georgia Escaramís & Eulàlia Martí

  7. Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain

    Franc Llorens & Daniela Diaz-Lucena

  8. Department of Neurology, National Reference Center for CJD Surveillance, University Medical Center Göttingen, Göttingen, Germany

    Franc Llorens

Authors
  1. Jordi Creus-Muncunill
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  2. Anna Guisado-Corcoll
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  3. Veronica Venturi
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  4. Lorena Pantano
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  5. Georgia Escaramís
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  6. Marta García de Herreros
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  7. Maria Solaguren-Beascoa
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  8. Ana Gámez-Valero
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  9. Cristina Navarrete
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  10. Mercè Masana
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  11. Franc Llorens
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  12. Daniela Diaz-Lucena
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  13. Esther Pérez-Navarro
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  14. Eulàlia Martí
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Contributions

JCM, AGC, VV, EPN, and EM designed the experimental approaches. JCM, AGC, VV, MGdH, MSB, AGV, CN, MM, FL, and DDL performed experiments. JCM, AGC, VV, LP, GE, EPN, and EM analyzed and interpreted the data. All authors made intellectual contributions to the experimental design and discussion. EPN and EM coordinated the study, and JCM and EM wrote the manuscript.

Corresponding authors

Correspondence to Esther Pérez-Navarro or Eulàlia Martí.

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The authors have declared that no conflict of interest exists.

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Creus-Muncunill, J., Guisado-Corcoll, A., Venturi, V. et al. Huntington’s disease brain-derived small RNAs recapitulate associated neuropathology in mice. Acta Neuropathol 141, 565–584 (2021). https://doi.org/10.1007/s00401-021-02272-9

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  • DOI: https://doi.org/10.1007/s00401-021-02272-9

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