Ruan Kai, Zhu Yi, Li Chong, Brazill Jennifer M, Zhai R Grace
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Nat Commun. 2015 Nov 30;6:10057. doi: 10.1038/ncomms10057.
Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved enzyme in the NAD synthetic pathway. It has also been identified as an effective and versatile neuroprotective factor. However, it remains unclear how healthy neurons regulate the dual functions of NMNAT and achieve self-protection under stress. Here we show that Drosophila Nmnat (DmNmnat) is alternatively spliced into two mRNA variants, RA and RB, which translate to protein isoforms with divergent neuroprotective capacities against spinocerebellar ataxia 1-induced neurodegeneration. Isoform PA/PC translated from RA is nuclear-localized with minimal neuroprotective ability, and isoform PB/PD translated from RB is cytoplasmic and has robust neuroprotective capacity. Under stress, RB is preferably spliced in neurons to produce the neuroprotective PB/PD isoforms. Our results indicate that alternative splicing functions as a switch that regulates the expression of functionally distinct DmNmnat variants. Neurons respond to stress by driving the splicing switch to produce the neuroprotective variant and therefore achieve self-protection.
烟酰胺单核苷酸腺苷酸转移酶（NMNAT）是NAD合成途径中的一种保守酶。它也被认为是一种有效且多功能的神经保护因子。然而，目前尚不清楚健康神经元如何调节NMNAT的双重功能并在应激状态下实现自我保护。在此我们表明，果蝇Nmnat（DmNmnat）可选择性剪接成两种mRNA变体，RA和RB，它们翻译出的蛋白质异构体对脊髓小脑共济失调1型诱导的神经退行性变具有不同的神经保护能力。从RA翻译而来的异构体PA/PC定位于细胞核，神经保护能力极小，而从RB翻译而来的异构体PB/PD位于细胞质，具有强大的神经保护能力。在应激状态下，RB在神经元中优先剪接，以产生具有神经保护作用的PB/PD异构体。我们的结果表明，选择性剪接起到了开关的作用，调节功能不同的DmNmnat变体的表达。神经元通过驱动剪接开关产生神经保护变体来应对应激，从而实现自我保护。
