Huntington’s disease brain-derived small RNAs recapitulate associated neuropathology in mice
نویسندگان
چکیده
Progressive motor alterations and selective death of striatal medium spiny neurons (MSNs) are key pathological hallmarks Huntington’s disease (HD), a neurodegenerative condition caused by CAG trinucleotide repeat expansion in the coding region huntingtin (HTT) gene. Most research has focused on pathogenic effects resultant protein product(s); however, growing evidence indicates that expanded repeats within mutant HTT mRNA derived small RNAs (sCAG) participate HD pathophysiology. The individual contribution versus RNA toxicity to pathophysiology remains largely uncharacterized role other classes (sRNA) strongly perturbed is uncertain. Here, we demonstrate sRNA produced putamen patients (HD-sRNA-PT) sufficient induce pathology vivo. Mice injected with HD-sRNA-PT show abnormalities, decreased levels HD-related proteins, disruption indirect pathway, strong transcriptional paralleling human pathology. Importantly, specific blockage sCAG mitigates neurotoxicity only limited extent. This observation prompted us identify species enriched neurotoxic potential. We detected high tRNA fragments (tRFs) putamen, validated potential an Alanine tRF vitro. These results highlight neurotoxic, suggest multiple contribute dysfunction general transcriptomic changes, favoring therapeutic strategies based sRNA-mediated toxicity.
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ژورنال
عنوان ژورنال: Acta Neuropathologica
سال: 2021
ISSN: ['1432-0533', '0001-6322']
DOI: https://doi.org/10.1007/s00401-021-02272-9