Pathological axonal death through a MAPK cascade that triggers a local energy deficit.
Pathological axonal death through a MAPK cascade that triggers a local energy deficit.
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DOI：
10.1016/j.cell.2014.11.053
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发表时间：
2015-01-15
期刊：
影响因子：
64.5
通讯作者：
Tessier-Lavigne M
中科院分区：
文献类型：
--
作者：
Yang J;Wu Z;Renier N;Simon DJ;Uryu K;Park DS;Greer PA;Tournier C;Davis RJ;Tessier-Lavigne M
轴突死亡破坏了神经回路的功能连接，是许多神经退行性疾病的关键特征。病理性轴突变性通常独立于已知的程序性死亡途径而发生，但其潜在的分子机制仍然很大程度上未知。使用创伤性损伤作为模型，我们系统地调查丝裂原活化蛋白激酶（MAPK）的家庭，并描绘了MAPK级联反应，代表轴突损伤的早期退行性反应。衔接蛋白Sarm 1是激活这种MAPK级联反应所必需的，并且这种Sarm 1-MAPK途径破坏轴突能量稳态，导致受损轴突物理分解之前ATP耗尽。保护性cytoNmnat 1/Wlds蛋白抑制MAPK级联反应的激活。此外，MKK 4是Sarm 1-MAPK通路中的关键组分，被AKT信号传导拮抗，AKT信号传导通过限制下游JNK信号传导的激活来调节退行性反应。我们的研究结果揭示了一种整合不同信号以指导病理性轴突变性的调节机制。
Axonal death disrupts functional connectivity of neural circuits and is a critical feature of many neurodegenerative disorders. Pathological axon degeneration often occurs independently of known programmed death pathways, but the underlying molecular mechanisms remain largely unknown. Using traumatic injury as a model, we systematically investigate mitogen-activated protein kinase (MAPK) families, and delineate a MAPK cascade that represents the early degenerative response to axonal injury. The adaptor protein Sarm1 is required for activation of this MAPK cascade, and this Sarm1-MAPK pathway disrupts axonal energy homeostasis, leading to ATP depletion before physical breakdown of damaged axons. The protective cytoNmnat1/Wlds protein inhibits activation of this MAPK cascade. Further, MKK4, a key component in the Sarm1-MAPK pathway, is antagonized by AKT signaling, which modulates the degenerative response by limiting activation of downstream JNK signaling. Our results reveal a regulatory mechanism that integrates distinct signals to instruct pathological axon degeneration.
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影响因子：
4.8
作者：
Park, HS;Kim, MS;Choi, EJ
通讯作者：
Choi, EJ
影响因子：
1.5
作者：
Tan, Yinfei;Dourdin, Nathalie;Greer, Peter A.
通讯作者：
Greer, Peter A.
DOI：
10.1523/jneurosci.3586-11.2012
发表时间：
2012-01-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Xiong X;Collins CA
通讯作者：
Collins CA
影响因子：
25
作者：
Miller, Bradley R.;Press, Craig;Daniels, Richard W.;Sasaki, Yo;Milbrandt, Jeffrey;DiAntonio, Aaron
通讯作者：
DiAntonio, Aaron
影响因子：
5.3
作者：
Press, Craig;Milbrandt, Jeffrey
通讯作者：
Milbrandt, Jeffrey