The Neurodegeneration Consortium, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Institute for Applied Cancer Science, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Int J Mol Sci. 2020 Jul 9;21(14):4849. doi: 10.3390/ijms21144849.
Dual leucine zipper kinase (DLK, Map3k12) is an axonal protein that governs the balance between degeneration and regeneration through its downstream effectors c-jun N-terminal kinase (JNK) and phosphorylated c-jun (p-c-Jun). In peripheral nerves DLK is generally inactive until induced by injury, after which it transmits signals to the nucleus via retrograde transport. Here we report that in contrast to this mode of regulation, in the uninjured adult mouse cerebellum, DLK constitutively drives nuclear p-c-Jun in cerebellar granule neurons, whereas in the forebrain, DLK is similarly expressed and active, but nuclear p-c-Jun is undetectable. When neurodegeneration results from mutant human tau in the rTg4510 mouse model, p-c-Jun then accumulates in neuronal nuclei in a DLK-dependent manner, and the extent of p-c-Jun correlates with markers of synaptic loss and gliosis. This regional difference in DLK-dependent nuclear p-c-Jun accumulation could relate to differing levels of JNK scaffolding proteins, as the cerebellum preferentially expresses JNK-interacting protein-1 (JIP-1), whereas the forebrain contains more JIP-3 and plenty of SH3 (POSH). To characterize the functional differences between constitutive- versus injury-induced DLK signaling, RNA sequencing was performed after DLK inhibition in the cerebellum and in the non-transgenic and rTg4510 forebrain. In all contexts, DLK inhibition reduced a core set of transcripts that are associated with the JNK pathway. Non-transgenic forebrain showed almost no other transcriptional changes in response to DLK inhibition, whereas the rTg4510 forebrain and the cerebellum exhibited distinct differentially expressed gene signatures. In the cerebellum, but not the rTg4510 forebrain, pathway analysis indicated that DLK regulates insulin growth factor-1 (IGF1) signaling through the transcriptional induction of IGF1 binding protein-5 (IGFBP5), which was confirmed and found to be functionally relevant by measuring signaling through the IGF1 receptor. Together these data illuminate the complex multi-functional nature of DLK signaling in the central nervous system (CNS) and demonstrate its role in homeostasis as well as tau-mediated neurodegeneration.
双亮氨酸拉链激酶（DLK，Map3k12）是一种轴突蛋白，通过其下游效应物 c-jun N 末端激酶（JNK）和磷酸化 c-jun（p-c-Jun）来调节退化和再生之间的平衡。在外周神经中，DLK 通常处于非活性状态，直到受到损伤诱导后，它才能通过逆行运输将信号传递到细胞核。在这里，我们报告称，与这种调节模式相反，在未受伤的成年小鼠小脑，DLK 持续驱动小脑颗粒神经元中的核 p-c-Jun，而在前脑中，DLK 同样表达且活跃，但核 p-c-Jun 无法检测到。当 rTg4510 小鼠模型中的突变人类 tau 导致神经退行性变时，p-c-Jun 然后以依赖于 DLK 的方式在神经元核中积累，并且 p-c-Jun 的积累程度与突触丢失和神经胶质增生的标志物相关。这种依赖于 DLK 的核 p-c-Jun 积累的区域性差异可能与 JNK 支架蛋白的水平有关，因为小脑优先表达 JNK 相互作用蛋白-1（JIP-1），而前脑包含更多的 JIP-3 和大量 SH3（POSH）。为了表征组成型与损伤诱导的 DLK 信号之间的功能差异，在小脑和非转基因和 rTg4510 前脑进行 DLK 抑制后进行了 RNA 测序。在所有情况下，DLK 抑制都会降低与 JNK 途径相关的一组核心转录本。非转基因前脑对 DLK 抑制几乎没有其他转录变化的反应，而 rTg4510 前脑和小脑则表现出不同的差异表达基因特征。在小脑，但不是 rTg4510 前脑，途径分析表明 DLK 通过转录诱导胰岛素样生长因子 1（IGF1）结合蛋白 5（IGFBP5）来调节 IGF1 信号，这通过测量 IGF1 受体的信号得到证实和发现是功能相关的。这些数据共同阐明了 DLK 信号在中枢神经系统（CNS）中的复杂多功能性质，并证明了它在稳态以及 tau 介导的神经退行性变中的作用。
