Suppression of premature transcription termination leads to reduced mRNA isoform diversity and neurodegeneration

Tight regulation of mRNA isoform expression is essential for neuronal development, maintenance, and function; however, the repertoire of proteins that govern isoform composition and abundance remains incomplete. Here, we show that the RNA kinase CLP1 regulates mRNA isoform expression through suppression of proximal cleavage and polyadenylation. We found that human stem-cell-derived motor neurons without CLP1 or with the disease-associated CLP1 p.R140H variant had distinct patterns of RNA-polymerase-II-associated cleavage and polyadenylation complex proteins that correlated with polyadenylation site usage. These changes resulted in imbalanced mRNA isoform expression of long genes important for neuronal function that were recapitulated in vivo. Strikingly, we observed the same pattern of reduced mRNA isoform diversity in 3′ end sequencing data from brain tissues of patients with neurodegenerative disease. Together, our results identify a previously uncharacterized role for CLP1 in mRNA 3′ end formation and reveal an mRNA misprocessing signature in neurodegeneration that may suggest a common mechanism of disease. [Display omitted] •CLP1 limits mRNA isoform diversity by suppressing proximal poly(A) site choice•CLP1 knockout and pathogenic CLP1 p.R140H have opposing effects on mRNA processing•Intronic polyadenylation evasion drives overexpression of long genes in neurons•Neurodegenerative diseases show a pattern of reduced mRNA 3′ end diversity LaForce et al. utilize motor neuron disease models to examine CLP1 function in mRNA 3′ end formation. CLP1 suppresses proximal polyadenylation to regulate mRNA isoform balance and maintain neuronal health. The authors find that diminished isoform diversity is a signature of neurodegenerative disease.