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Publication

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

Neuron | 2022

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.

Pubmed ID: 35139363 RIS Download

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Associated grants

Agency: NINDS NIH HHS, United States
Id: R01 NS123524
Agency: NINDS NIH HHS, United States
Id: F31 NS122207
Agency: NICHD NIH HHS, United States
Id: R00 HD082337
Agency: NINDS NIH HHS, United States
Id: R01 NS121374
Agency: NIGMS NIH HHS, United States
Id: R35 GM144114
Agency: NINDS NIH HHS, United States
Id: R01 NS114510
Agency: NINDS NIH HHS, United States
Id: K01 NS116119
Agency: NIGMS NIH HHS, United States
Id: T32 GM007250

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