Mutant messenger RNA (mRNA) and protein contribute to the clinical manifestation of many repeat-associated neurological disorders, with the presence of nuclear RNA clusters being a common pathological feature. Yet, investigations into Huntington's disease-caused by a CAG repeat expansion in exon 1 of the () gene-have primarily focused on toxic protein gain-of-function as the primary disease-causing feature. To date, mutant mRNA has not been identified as an hallmark of Huntington's disease. Here, we report that, in two Huntington's disease mouse models (YAC128 and BACHD-97Q-ΔN17), mutant mRNA is retained in the nucleus. Widespread formation of large mRNA clusters (∼0.6-5 µm) occurred in 50-75% of striatal and cortical neurons. Cluster formation was independent of age and driven by expanded repeats. Clusters associate with chromosomal transcriptional sites and quantitatively co-localize with the aberrantly processed N-terminal exon 1-intron 1 mRNA isoform, . mRNA clusters are observed in a subset of neurons from human Huntington's disease post-mortem brain and are likely caused by somatic expansion of repeats. In YAC128 mice, clusters, but not individual mRNA, are resistant to antisense oligonucleotide treatment. Our findings identify mutant / mRNA clustering as an early, robust molecular signature of Huntington's disease, providing evidence that Huntington's disease is a repeat expansion disease with mRNA involvement.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9707646PMC
http://dx.doi.org/10.1093/braincomms/fcac248DOI Listing

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