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Title: Huntington's disease brain-derived small RNAs recapitulate associated neuropathology in wild-type mice
Author: Creus Muncunill, Jordi
Guisado Corcoll, Anna
Venturi, Veronica
Pantano, Lorena
Escaramís Babiano, Geòrgia
Gardia de Herreros, Marta
Solanguren-Beascoa, Maria
Gámez Valero, Ana
Navarrete, Cristina
Masana Nadal, Mercè
Llorens Torres, Franc
Diaz-Lucena, Daniela
Pérez Navarro, Esther
Martí, Eulàlia
Keywords: Corea de Huntington
Models animals en la investigació
Huntington's chorea
Animal models in research
Issue Date: Apr-2021
Publisher: Springer Verlag
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.
Note: Versió postprint del document publicat a:
It is part of: Acta Neuropathologica, 2021, vol. 141, num. 4, p. 565-584
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ISSN: 0001-6322
Appears in Collections:Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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