A local mechanism mediates NAD-dependent protection of axon degeneration.
A local mechanism mediates NAD-dependent protection of axon degeneration.
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DOI：
10.1083/jcb.200504028
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发表时间：
2005-08-01
期刊：
影响因子：
--
通讯作者：
He Z
中科院分区：
文献类型：
--
作者：
Wang J;Zhai Q;Chen Y;Lin E;Gu W;McBurney MW;He Z
轴突变性常见于神经退行性疾病和周围神经病。对轴突变性机制的重要认识源于以下发现：在过度表达与烟酰胺腺嘌呤二核苷酸(NAD)合成酶烟酰胺单核苷酸腺基转移酶(Nmnat1)的融合蛋白的Weller变性缓慢(Wlds)小鼠中，横断轴突的退化被延迟。虽然Wlds和Nmnat1本身在神经元培养中都具有防止轴突退化的功能，但Nmnat1和NAD介导的轴突保护的潜在机制仍然很大程度上尚不清楚。我们证明了在退行性轴突中NAD水平降低，阻止这种轴突NAD下降有效地保护轴突免受退变。为了支持局部保护机制，我们证明了外源性应用NAD或其前体烟酰胺可以防止已从其胞体分离的轴突段的退化。此外，我们提供的证据表明，这种Nmnat1/NAD介导的保护主要是通过它们对局部生物能量学的影响来介导的。综上所述，我们的结果提示了轴突退变的一种新的分子途径。
Axon degeneration occurs frequently in neurodegenerative diseases and peripheral neuropathies. Important insight into the mechanisms of axon degeneration arose from findings that the degeneration of transected axons is delayed in Wallerian degeneration slow (Wlds) mice with the overexpression of a fusion protein with the nicotinamide adenine dinucleotide (NAD) synthetic enzyme, nicotinamide mononucleotide adenylyltransferase (Nmnat1). Although both Wlds and Nmnat1 themselves are functional in preventing axon degeneration in neuronal cultures, the underlying mechanism for Nmnat1- and NAD-mediated axon protection remains largely unclear. We demonstrate that NAD levels decrease in degenerating axons and that preventing this axonal NAD decline efficiently protects axons from degeneration. In support of a local protective mechanism, we show that the degeneration of axonal segments that have been separated from their soma could be prevented by the exogenous application of NAD or its precursor nicotinamide. Furthermore, we provide evidence that such Nmnat1/NAD-mediated protection is primarily mediated by their effects on local bioenergetics. Together, our results suggest a novel molecular pathway for axon degeneration.
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