@article{304697ce02f24f698fc59cbfd0fdf07c,
title = "MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing",
abstract = "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 the 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. NMNAT pre-mRNA is preferentially spliced to RA in basal conditions, whereas 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.",
keywords = "Biological Sciences, Cell Biology, Molecular Biology",
author = "Joun Park and Yi Zhu and Xianzun Tao and Brazill, {Jennifer M.} and Chong Li and Stefan Wuchty and Zhai, {R. Grace}",
note = "Funding Information: Our model predicts a novel role for miR-1002's regulation of NMNAT ( Figure 7 ). In basal conditions, NMNAT pre-mRNA is spliced to RA with a slight preference via stem-loop formation ( Ruan et al., 2015 ). Under stress, miR-1002 is upregulated and switches the splicing of newly transcribed NMNAT pre-mRNA almost exclusively to RB. Given the robust neuroprotective function of NMNAT isoform PD, miR-1002-mediated switch of alternative splicing enhances neuronal resistance to stress and confers organismal resilience. This is supported by the reduced thermotolerance observed in ΔmiR-1002 flies. The modest reduction in thermotolerance suggests that miR-1002 is just one of the key players in the complex stress response network. Many other genes and proteins, including heat shock proteins, have been found to contribute to stress resistance ( Bartelt-Kirbach et al., 2016; Jo et al., 2017; Kawasaki et al., 2016; Morrow et al., 2016; Shukla et al., 2014 ). Importantly, our study found that overexpression of miR-1002 in neurons was sufficient to shift alternative splicing toward RB in vivo , further substantiating the role of miR-1002 in enhancing NMNAT-mediated neuroprotection. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = sep,
day = "27",
doi = "10.1016/j.isci.2019.08.052",
language = "English (US)",
volume = "19",
pages = "1048--1064",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
}