Ulk1 Governs Nerve Growth Factor/TrkA Signaling by Mediating Rab5 GTPase Activation in Porcine Hemagglutinating Encephalomyelitis Virus-Induced Neurodegenerative Disorders
Ulk1 Governs Nerve Growth Factor/TrkA Signaling by Mediating Rab5 GTPase Activation in Porcine Hemagglutinating Encephalomyelitis Virus-Induced Neurodegenerative Disorders
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Ulk1 通过介导猪血凝性脑脊髓炎病毒引起的神经退行性疾病中 Rab5 GTP 酶激活来控制神经生长因子/TrkA 信号转导
DOI：
10.1128/jvi.00325-18
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发表时间：
2018-08-01
影响因子：
5.4
通讯作者：
He, Wenqi
中科院分区：
文献类型：
--
作者：
Li, Zi;Zhao, Kui;He, Wenqi
猪血凝性脑脊髓炎病毒（PHEV）是一种嗜神经冠状病毒，靶向神经系统中的神经元增殖，经常留下严重的神经变性。结构可塑性障碍发生在PHEV感染的神经元的轴突、树突和树突棘中，并且该神经过程的功能障碍可能导致神经病理学病变，但是机制仍然不确定。进一步了解中枢神经系统中PHEV感染的神经学表现可能有助于了解神经发育和神经退行性疾病，这可能有助于靶向治疗方法。我们研究的意义在于确定Ulk 1相关的神经退行性机制，重点关注Ulk 1在长距离营养信号内体运输中的调节功能，从而解释与PHEV侵略相关的神经突生长和存活的进行性失败。这是第一份报告，以确定一个机制之间的联系，从内吞途径和PHEV诱导的中枢神经系统疾病的神经发病机制的信号改变。摘要猪血凝性脑脊髓炎病毒（PHEV）是一种高度神经毒性的冠状病毒，可引起中枢神经系统（CNS）的神经功能障碍，但其神经病理机制尚不清楚。我们报告说，Unc 51样激酶1（Ulk 1/Unc51.1）是一个关键的调节PHEV诱导的神经系统疾病和功能，选择性地控制神经生长因子（NGF）/TrkA内体运输的启动。我们首先通过PHEV感染小鼠模型的组织病理学评价确定了Ulk 1的功能，在该模型中，神经元损失伴随着Ulk 1表达的抑制。原代皮层神经元的形态发生评估显示，Ulk 1的过度表达或突变调节神经突生长，侧枝发芽和内体转运。同样，Ulk 1表达在PHEV感染后降低，表明神经变性和功能性Ulk 1缺陷之间存在相关性。然后，我们发现Ulk 1与TrkA和早期内体标记Rab 5形成多蛋白复合物，并且Ulk 1缺陷导致NGF/TrkA内吞作用的阻断或通过Rab 5 GTdR的组成性激活导致pTrkA的过早降解。进一步的研究确定Rab 5突变体的异位表达诱导激活的pTrkA的异常内体积累，证明Ulk 1-TrkA-NGF信号传导靶向PHEV感染的神经退行性过程中的逆行转运途径依赖于Rab 5 GTdR活性。因此，我们描述了PHEV驱动的神经元缺陷的长距离信号传导机制，并提出这种Ulk 1抑制可能导致激活的Rab 5内体内有限的NGF/TrkA逆行信号传导，解释了神经突生长和存活的进行性失败。猪血凝性脑脊髓炎病毒（PHEV）是一种嗜神经冠状病毒，靶向神经系统中的神经元增殖，经常留下严重的神经变性。结构可塑性障碍发生在PHEV感染的神经元的轴突、树突和树突棘中，并且该神经过程的功能障碍可能导致神经病理学病变，但是机制仍然不确定。进一步了解中枢神经系统中PHEV感染的神经学表现可能有助于了解神经发育和神经退行性疾病，这可能有助于靶向治疗方法。我们研究的意义在于确定Ulk 1相关的神经退行性机制，重点关注Ulk 1在长距离营养信号内体运输中的调节功能，从而解释与PHEV侵略相关的神经突生长和存活的进行性失败。这是第一份报告，以确定一个机制之间的联系，从内吞途径和PHEV诱导的中枢神经系统疾病的神经发病机制的信号改变。
Porcine hemagglutinating encephalomyelitis virus (PHEV) is a neurotropic coronavirus and targets neurons in the nervous system for proliferation, frequently leaving behind grievous neurodegeneration. Structural plasticity disorders occur in the axons, dendrites, and dendritic spines of PHEV-infected neurons, and dysfunction of this neural process may contribute to neurologic pathologies, but the mechanisms remain undetermined. Further understanding of the neurological manifestations underlying PHEV infection in the CNS may provide insights into both neurodevelopmental and neurodegenerative diseases that may be conducive to targeted approaches for treatment. The significance of our research is in identifying an Ulk1-related neurodegenerative mechanism, focusing on the regulatory functions of Ulk1 in the transport of long-distance trophic signaling endosomes, thereby explaining the progressive failure of neurite outgrowth and survival associated with PHEV aggression. This is the first report to define a mechanistic link between alterations in signaling from endocytic pathways and the neuropathogenesis of PHEV-induced CNS disease. ABSTRACT Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurovirulent coronavirus and causes neurological dysfunction in the central nervous system (CNS), but the neuropathological mechanism of PHEV remains poorly understood. We report that Unc51-like kinase 1 (Ulk1/Unc51.1) is a pivotal regulator of PHEV-induced neurological disorders and functions to selectively control the initiation of nerve growth factor (NGF)/TrkA endosome trafficking. We first identified the function of Ulk1 by histopathologic evaluation in a PHEV-infected mouse model in which neuronal loss was accompanied by the suppression of Ulk1 expression. Morphogenesis assessments in the primary cortical neurons revealed that overexpression or mutations of Ulk1 modulated neurite outgrowth, collateral sprouting, and endosomal transport. Likewise, Ulk1 expression was decreased following PHEV infection, suggesting that there was a correlation between the neurodegeneration and functional Ulk1 deficiency. We then showed that Ulk1 forms a multiprotein complex with TrkA and the early endosome marker Rab5 and that Ulk1 defects lead to either blocking of NGF/TrkA endocytosis or premature degradation of pTrkA via constitutive activation of the Rab5 GTPase. Further investigation determined that the ectopic expression of Rab5 mutants induces aberrant endosomal accumulation of activated pTrkA, proving that targeting of Ulk1-TrkA-NGF signaling to the retrograde transport route in the neurodegenerative process that underlies PHEV infection is dependent on Rab5 GTPase activity. Therefore, we described a long-distance signaling mechanism of PHEV-driven deficits in neurons and suggested that such Ulk1 repression may result in limited NGF/TrkA retrograde signaling within activated Rab5 endosomes, explaining the progressive failure of neurite outgrowth and survival. IMPORTANCE Porcine hemagglutinating encephalomyelitis virus (PHEV) is a neurotropic coronavirus and targets neurons in the nervous system for proliferation, frequently leaving behind grievous neurodegeneration. Structural plasticity disorders occur in the axons, dendrites, and dendritic spines of PHEV-infected neurons, and dysfunction of this neural process may contribute to neurologic pathologies, but the mechanisms remain undetermined. Further understanding of the neurological manifestations underlying PHEV infection in the CNS may provide insights into both neurodevelopmental and neurodegenerative diseases that may be conducive to targeted approaches for treatment. The significance of our research is in identifying an Ulk1-related neurodegenerative mechanism, focusing on the regulatory functions of Ulk1 in the transport of long-distance trophic signaling endosomes, thereby explaining the progressive failure of neurite outgrowth and survival associated with PHEV aggression. This is the first report to define a mechanistic link between alterations in signaling from endocytic pathways and the neuropathogenesis of PHEV-induced CNS disease.