Wallerian Degeneration Is Executed by an NMN-SARM1-Dependent Late Ca2+ Influx but Only Modestly Influenced by Mitochondria
Wallerian Degeneration Is Executed by an NMN-SARM1-Dependent Late Ca2+ Influx but Only Modestly Influenced by Mitochondria
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DOI：
10.1016/j.celrep.2015.11.032
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发表时间：
2015-12-22
期刊：
影响因子：
8.8
通讯作者：
Conforti, Laura
中科院分区：
文献类型：
--
作者：
Loreto, Andrea;Di Stefano, Michele;Conforti, Laura
轴突损伤导致NAD生物合成酶NMNA2迅速耗尽，其底物NMN水平升高。我们提出了NMN在沃勒变性中的关键作用，但下游事件及其与其他介体的关系仍不清楚。在体外和体内，我们表明，轴突切断导致轴突内钙离子的晚期增加，而这种增加被药物或遗传降低的NMN水平所消除。NMN需要前退变蛋白Sarm1来刺激钙离子内流和轴突退变。虽然抑制NMN的合成和Sarm1的缺失阻止了钙的升高，并保护了轴突的完整性，但它们无法阻止早期线粒体的动态变化。此外，去极化线粒体不会改变沃勒变性的速度。这些数据表明，NMN和Sarm1在共同的通路中起作用，最终导致轴突内钙的增加和碎裂，并将线粒体功能障碍从这一途径中分离出来，阐明了哪些步骤可能是最有效的治疗靶点。
Axon injury leads to rapid depletion of NAD-biosynthetic enzyme NMNAT2 and high levels of its substrate, NMN. We proposed a key role for NMN in Wallerian degeneration but downstream events and their relationship to other mediators remain unclear. Here, we show, in vitro and in vivo, that axotomy leads to a late increase in intra-axonal Ca2+, abolished by pharmacological or genetic reduction of NMN levels. NMN requires the pro-degenerative protein SARM1 to stimulate Ca2+ influx and axon degeneration. While inhibition of NMN synthesis and SARM1 deletion block Ca2+ rise and preserve axonal integrity, they fail to prevent early mitochondrial dynamic changes. Furthermore, depolarizing mitochondria does not alter the rate of Wallerian degeneration. These data reveal that NMN and SARM1 act in a common pathway culminating in intra-axonal Ca2+ increase and fragmentation and dissociate mitochondrial dysfunctions from this pathway, elucidating which steps may be most effective as targets for therapy.