Defective linear and circular RNAs biogenesis in Huntington’s disease: CAG repeat expansion hijacks neuronal splicing

Abstract

Alternative splicing (AS) appears to be altered in Huntington's disease (HD), but its significance for early, pre-symptomatic disease stages has not been inspected. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a strong correlation between Htt CAG repeat length and increased aberrant linear AS, specifically affecting neural progenitors and, in vivo, the striatum prior to overt behavioral phenotypes stages. Remarkably, expanded Htt CAG repeats reflect on a previously neglected, global impairment of back-splicing, leading to decreased circular RNAs production in neural progenitors. Though the mechanisms of this dysregulation remain uncertain, our study unveils network of transcriptionally altered micro-RNAs and RNA-binding proteins (CELF, hnRNPS, PTBP, SRSF) which, in turn, might influence the AS machinery, primarily in neural cells. We suggest that this unbalanced expression of linear and circular RNAs might result in altered neural fitness, contributing to HD striatal vulnerability.

Current Diagnostic Methods and Non-Coding RNAs as Possible Biomarkers in Huntington’s Disease

“…Finally, circRNAs also represent a new category of promising RNA biomarkers. A recent study detected 23 dysregulated circRNAs in a murine cell line, having functions associated with the dopaminergic synapse [ 74 ], while our work, shows dysregulation of circRNAs in neuronal progenitors expressing aberrantly long Htt CAG repeat [ 75 ]. CircRNA detection and dysregulation in the human blood samples from HD patients remains a still unexplored research area.…”

“…Their function was associated with dopaminergic synapses, MAPK and long-term depression, all of which were previously related to HD pathogenesis [ 74 ]. On the other hand, our genome-wide analyses using mouse knock-in neuronal progenitors series clearly demonstrated a reduction in more than 500 circRNAs following the expression of the expanded CAG alleles [ 75 ]. See also Table 1 for general summary.…”

News from around the RNA world: new avenues in RNA biology, biotechnology and therapeutics from the 2022 SIBBM meeting

“…Biagioli described that the CAG expansion in HTT correlates with alterations in splicing events in neural progenitors. The work sheds light on new possible mechanisms that are dysregulated in Huntington's disease and the regulatory interactions with miRNAs and RBPs ( Ayyildiz et al, 2021 ).…”