Data-driven model reveals increased stability of CAG-expanded huntingtin RNA due to MID1 binding

RNA-binding proteins (RBP) are important regulators of RNA metabolism. In neurodegenerative disorders such as Huntington’s Disease (HD), disrupted RBP-RNA interactions contribute to neuronal dysfunction. One such RBP, Midline 1 (MID1), has been shown to aberrantly associate with mutant huntingtin (Htt) RNA, enhancing its translation, yet the mechanism driving this effect remains unknown. Here, we develop a computational model to understand the role of MID1. Based on previously published data, our model predicts that MID1 increases the stability of the Htt RNA. We experimentally validate this prediction, showing that overexpression of MID1 significantly prolongs the half-life of mutant Htt RNA. Furthermore, we evaluate model refinements, including clustering of MID1-bound RNA, which allow capturing all key observations in the data. Together, we provide a data-driven framework that underlines the importance of RBP-RNA interaction in post-transcriptional regulation. This framework also shows how individual molecular reactions jointly determine RNA stability and protein levels in HD.Author summary: Huntington’s Disease is a severe brain disorder caused by a mutation that makes a part of the huntingtin gene much longer than normal. This change affects how the gene’s RNA interacts with proteins that normally control how long RNAs live and how much protein they produce. One of these proteins, called MID1, attaches more strongly to the mutant huntingtin RNA and increases the amount of mutant huntingtin protein, which may worsen the disease.