RT Journal Article
SR Electronic
T1 MicroRNA miR-1002 enhances NMNAT-mediated stress response by modulating alternative splicing
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 641944
DO 10.1101/641944
A1 Joun Park
A1 Yi Zhu
A1 Xianzun Tao
A1 Jennifer M. Brazill
A1 Chong Li
A1 Stefan Wuchty
A1 R. Grace Zhai
YR 2019
UL http://biorxiv.org/content/early/2019/06/13/641944.abstract
AB Understanding endogenous regulation of stress resistance and homeostasis maintenance is critical to developing neuroprotective therapies. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved essential enzyme that confers extraordinary protection and stress resistance in many neurodegenerative disease models. Drosophila Nmnat is alternatively spliced to two mRNA variants, RA and RB. RB translates to protein isoform PD with robust protective activity and is upregulated upon stress to confer enhanced neuroprotection. The mechanisms regulating alternative splicing and stress response of NMNAT remain unclear. We have discovered a Drosophila microRNA, dme-miR-1002, which promotes the splicing of NMNAT pre-mRNA to RB by disrupting a pre-mRNA stem-loop structure. While NMNAT pre-mRNA is preferentially spliced to RA in basal conditions, miR-1002 enhances NMNAT PD-mediated stress protection by binding via RISC component Argonaute1 to the pre-mRNA, facilitating the splicing switch to RB. These results outline a new process for microRNAs in regulating alternative splicing and modulating stress resistance.