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

Affiliation

Creus-Muncunill J(#)(1)(2)(3)(4), Guisado-Corcoll A(#)(1)(2)(3), Venturi V(5), Pantano L(6), Escaramís G(1)(7), García de Herreros M(1)(2)(3), Solaguren-Beascoa M(1), Gámez-Valero A(1), Navarrete C(5), Masana M(1)(2)(3), Llorens F(3)(8)(9), Diaz-Lucena D(3)(8), Pérez-Navarro E(10)(11)(12), Martí E(13)(14)(15).
Author information:
(1)Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Casanova 143, Barcelona, Catalonia, Spain.
(2)Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), Barcelona, Catalonia, Spain.
(3)Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
(CIBERNED), Barcelona, Catalonia, Spain.
(4)Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
(5)Centre for Genomic Regulation
(CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, Barcelona, Catalonia, Spain.
(6)Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
(7)Centro de Investigación Biomédica en Red sobre Epidemiología y Salud Pública
(CIBERESP), Barcelona, Catalonia, Spain.
(8)Bellvitge Biomedical Research Institute
(IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
(9)Department of Neurology, National Reference Center for CJD Surveillance, University Medical Center Göttingen, Göttingen, Germany.
(10)Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Casanova 143, Barcelona, Catalonia, Spain. [Email]
(11)Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), Barcelona, Catalonia, Spain. [Email]
(12)Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
(CIBERNED), Barcelona, Catalonia, Spain. [Email]
(13)Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Casanova 143, Barcelona, Catalonia, Spain. [Email]
(14)Centre for Genomic Regulation
(CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, Barcelona, Catalonia, Spain. [Email]
(15)Centro de Investigación Biomédica en Red sobre Epidemiología y Salud Pública
(CIBERESP), Barcelona, Catalonia, Spain. [Email]
(#)Contributed equally

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.