Avetisyan Adel, Barria Romina, Sheehan Amy, Freeman Marc R
bioRxiv. 2024 Nov 28:2024.10.29.620922. doi: 10.1101/2024.10.29.620922.
How neurons to sense when they are terminally dysfunctional and activate neurodegeneration remains poorly defined. The pro-degenerative NAD hydrolase dSarm/SARM1 can act as a metabolic sensor by detecting pathological changes in NAD /NMN and subsequently induce catastrophic axon degeneration. Here we show with-no-lysine kinase (dWnk), which can directly sense Cl , K and osmotic pressure, is required for neurodegeneration induced by depletion of the NAD biosynthetic enzyme dNmnat. dWnk functions in parallel to dSarm and acts through the downstream kinase Frayed to promote axon degeneration and neuronal cell death. dWnk and dSarm ultimately converge on the BTB-Back domain molecule Axundead (Axed) to execute neurodegeneration. Our work argues that neurons use direct sensors of both metabolism (dSarm/SARM1) and ionic/osmotic status (dWnk) to evaluate cellular health and, when dysfunctional, promote neurodegeneration though a common axon death signaling molecule, Axundead.
神经元如何感知自身处于终末功能障碍状态并激活神经退行性变，目前仍不清楚。促退行性NAD水解酶dSarm/SARM1可通过检测NAD⁺/NMN的病理变化作为代谢传感器，随后诱导灾难性轴突退变。在此，我们发现无赖氨酸激酶（dWnk），其可直接感知氯离子、钾离子和渗透压，是由NAD⁺生物合成酶dNmnat缺失诱导的神经退行性变所必需的。dWnk与dSarm平行发挥作用，并通过下游激酶Frayed促进轴突退变和神经元细胞死亡。dWnk和dSarm最终汇聚于BTB-背域分子Axundead（Axed）以执行神经退行性变。我们的研究表明，神经元利用代谢（dSarm/SARM1）和离子/渗透压状态（dWnk）的直接传感器来评估细胞健康状况，当功能失调时，通过共同的轴突死亡信号分子Axundead促进神经退行性变。
