Deregulated Splicing Is a Major Mechanism of RNA-Induced Toxicity in Huntington's Disease

Huntington’s disease-specific mis-splicing captured by human-mouse intersect-RNA-seq unveils pathogenic effectors and reduced splicing factors

“…Pathological expanded CAG-containing mRNAs adopt a hairpin conformation 37 and some of the altered splicing factors detected here are likely to be affected by direct and aberrant interaction with expanded CAG mRNA. This is in fact the case of U2AF2 15,22 and HNRNPC 15 . Both U2AF2 and HNRNPC bind to U-rich motifs, as also do TIA1 and the ELAVL family, all identified here as misregulated in human HD patients and the mouse model.…”

“…However, when it is not properly executed, AS leads to mis-splicing, which may result in proteins with altered function and stability 1 . A number of splicing factors and other RNAbinding proteins (RBPs) are responsible for proper regulation of AS 2 , and growing evidence has implicated mis-splicing in a range of pathologies such as cancer 3 , muscular dystrophies 4 , autism 5,6 and neurodegenerative diseases 7 such as Alzheimer´s disease 8,9 , amyotrophic lateral sclerosis 10,11 and Huntington's disease [12][13][14][15] . Next-generation RNA sequencing (RNA-seq) has boosted investigation of global mis-splicing in diseased tissue.…”

“…Similar pathogenic CAG mutations in different genes cause multiple dominant spinocerebellar ataxias (SCAs), including SCA-1, -2, -3, -6, -7 and -17 18 and there is evidence of toxicity being mediated by both the expanded CAG-containing mRNAs and the polyQ-containing proteins 19,20 . The proteins that interact with expanded CAG mRNA include splicing factors such as MBNL1 21 , U2AF2 22 and SRSF6 15,23 , the latter being also sequestered into the characteristic polyQ inclusion bodies found 4 in HD brains 13 . All this has led to the proposal that splicing alterations may, at least in part, underlie HD [12][13][14][15] .…”

“…The proteins that interact with expanded CAG mRNA include splicing factors such as MBNL1 21 , U2AF2 22 and SRSF6 15,23 , the latter being also sequestered into the characteristic polyQ inclusion bodies found 4 in HD brains 13 . All this has led to the proposal that splicing alterations may, at least in part, underlie HD [12][13][14][15] . In fact, hypothesis-driven studies have identified two mis-splicing events in the etiology of HD.…”

Altered Levels and Isoforms of Tau and Nuclear Membrane Invaginations in Huntington’s Disease

“…It was bioinformatically predicted (Sathasivam et al, 2013) and biochemically confirmed (Schilling et al, 2019) that the splicing factor SRSF6 can bind CAG RNA repeats and this leads to incomplete splicing of Htt RNA and to production of a small form of Htt known as exon 1-Htt (Sathasivam et al, 2013). Besides, SRSF6 was indeed found altered in the striatum of HD patients and in the R6/1 mouse model of the disease, as it gets sequestered into mHtt inclusions (Fernández-Nogales et al, 2014).…”