Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress.
Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress.
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DOI：
10.1038/ncomms10057
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发表时间：
2015-11-30
影响因子：
16.6
通讯作者：
Zhai RG
中科院分区：
文献类型：
--
作者：
Ruan K;Zhu Y;Li C;Brazill JM;Zhai RG
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. Nicotinamide mononucleotide adenylyltransferase (NMNAT) acts in the NAD biosynthesis pathway and has neuroprotective activity. Ruan et al. show that the neuroprotective activity of NMNAT is restricted to a splice variant of the enzyme, and that this variant is preferentially spliced in response to stress.
