PRMT5 promotes full-length HTT expression by repressing multiple proximal intronic polyadenylation sites

Yadav, Manisha, AlQazzaz, Mona A., Ciamponi, Felipe E., Ho, Jolene C., Maron, Maxim I., Sababi, Aiden M., MacLeod, Graham, Ahmadi, Moloud, Bullivant, Garrett, Tano, Vincent, Langley, Sarah R. ORCID: https://orcid.org/0000-0003-4419-476X, Sánchez-Osuna, María, Sachamitr, Patty, Kushida, Michelle, Bardile, Costanza Ferrari, Pouladi, Mahmoud A., Kurtz, Rebecca, Richards, Laura, Pugh, Trevor, Tyers, Mike, Angers, Stephane, Dirks, Peter B., Bader, Gary D., Truant, Ray, Massirer, Katlin B., Barsyte-Lovejoy, Dalia, Shechter, David, Harding, Rachel J., Arrowsmith, Cheryl H. and Prinos, Panagiotis 2025. PRMT5 promotes full-length HTT expression by repressing multiple proximal intronic polyadenylation sites. Nucleic Acids Research 53 (8) , gkaf347. 10.1093/nar/gkaf347

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Abstract

Expansion of the CAG trinucleotide repeat tract in exon 1 of the Huntingtin (HTT) gene causes Huntington’s disease (HD) through the expression of a polyglutamine-expanded form of the HTT protein. This mutation triggers cellular and biochemical pathologies, leading to cognitive, motor, and psychiatric symptoms in HD patients. Targeting HTT splicing with small molecule drugs is a compelling approach to lowering HTT protein levels to treat HD, and splice modulators are currently being tested in the clinic. Here, we identify PRMT5 as a novel regulator of HTT messenger RNA (mRNA) splicing and alternative polyadenylation. PRMT5 inhibition disrupts the splicing of HTT introns 9 and 10, leading to the activation of multiple proximal intronic polyadenylation sites within these introns and promoting premature termination, cleavage, and polyadenylation of the HTT mRNA. This suggests that HTT protein levels may be lowered due to this mechanism. We also detected increasing levels of these truncated HTT transcripts across a series of neuronal differentiation samples, which correlated with lower PRMT5 expression. Notably, PRMT5 inhibition in glioblastoma stem cells potently induced neuronal differentiation. We posit that PRMT5-mediated regulation of intronic polyadenylation, premature termination, and cleavage of the HTT mRNA modulates HTT expression and plays an important role during neuronal differentiation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Biosciences
Publisher:	Oxford University Press
ISSN:	0305-1048
Date of First Compliant Deposit:	7 May 2025
Date of Acceptance:	16 April 2025
Last Modified:	19 May 2025 11:15
URI:	https://orca.cardiff.ac.uk/id/eprint/178130

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