A role for the p75 neurotrophin receptor in Schwann cell regulation of sensory neurons

p75 神经营养素受体在雪旺细胞调节感觉神经元中的作用

基本信息

批准号：
10417076
负责人：
Bruce D Carter
金额：
$ 50.91万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417076
关键词：
7-dehydrocholesterol 7-dehydrocholesterol reductase AVIL gene Affect Afferent Neurons Affinity Apoptosis Attenuated Axon Behavior Binding Biogenesis Biological Assay Brain-Derived Neurotrophic Factor Clinical Complex Data Development Diabetes Mellitus Diabetic Neuropathies Disease ERBB2 Signaling Pathway ERBB2 gene Esthesia Etiology FRAP1 gene Family Fatty Acids Growth Growth Factor Human Impairment Lead Link Lipids Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Metabolic Mitochondria Motor Neurons Mus Mutant Strains Mice Myelin NGFR Protein Nerve Nerve Degeneration Neuroglia Neurons Nociception Oxidative Stress Pain Pathway interactions Peripheral Peripheral Nervous System Diseases Persons Population Population Decreases Production Proprioception Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Role Schwann Cells Sensory Signal Transduction Spinal Cord Spinal Ganglia Testing United States acylcarnitine axon growth axonal degeneration cholesterol biosynthesis conditional knockout in vivo insight knockout animal lipid metabolism mitochondrial dysfunction neuron apoptosis neuron loss neurotoxic neurotrophic factor novel oxidation oxidative damage transcriptional coactivator p75

7-dehydrocholesterol 7-dehydrocholesterol reductase AVIL gene Affect Afferent Neurons Affinity Apoptosis Attenuated Axon Behavior Binding Biogenesis Biological Assay Brain-Derived Neurotrophic Factor Clinical Complex Data Development Diabetes Mellitus Diabetic Neuropathies Disease ERBB2 Signaling Pathway ERBB2 gene Esthesia Etiology FRAP1 gene Family Fatty Acids Growth Growth Factor Human Impairment Lead Link Lipids Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Metabolic Mitochondria Motor Neurons Mus Mutant Strains Mice Myelin NGFR Protein Nerve Nerve Degeneration Neuroglia Neurons Nociception Oxidative Stress Pain Pathway interactions Peripheral Peripheral Nervous System Diseases Persons Population Population Decreases Production Proprioception Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Role Schwann Cells Sensory Signal Transduction Spinal Cord Spinal Ganglia Testing United States acylcarnitine axon growth axonal degeneration cholesterol biosynthesis conditional knockout in vivo insight knockout animal lipid metabolism mitochondrial dysfunction neuron apoptosis neuron loss neurotoxic neurotrophic factor novel oxidation oxidative damage transcriptional coactivator p75

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项目摘要

Peripheral neuropathy is a debilitating and often painful condition associated with a wide variety of diseases. Unfortunately, in most cases, there is no treatment for the neurodegeneration, highlighting the need to better understand the mechanisms regulating axon integrity and neuron viability. One key regulator of neuron survival and axon growth is the family of neurotrophins, which act through binding to the Trk family of receptor tyrosine kinases and the p75 neurotrophin receptor. Activation of the Trks promotes survival and growth, while stimulation of p75 can induce apoptosis and axon degeneration. However, p75 can also form a high affinity complex with the Trks that mediates pro-survival signaling. Reduced neurotrophin signaling in neurons leads to impaired sensory function in humans and complete loss of neurotrophin signaling leads to extensive neuronal apoptosis. For example, mice lacking p75 lose ~50% of the sensory neurons in their dorsal root ganglia (DRG), which was presumed to be due to a reduction in the p75-Trk complex in the neurons, leading to inadequate trophic support. However, p75 is also expressed in Schwann cells and we made the surprising discovery that selective deletion of p75 in Schwann cells resulted in a 30% reduction in DRG neurons and decreased heat sensitivity. These results support growing evidence that glial cells are critical modulators of neuronal function and viability. We also found altered lipid metabolism in p75-/- nerves, with a marked increase in oxysterols and acylcarnitines, which are neurotoxic. Therefore, we hypothesize that p75 null Schwann cells release these lipids, leading to neurodegeneration. In considering how p75 could regulate lipid metabolism, we identified a novel complex between p75 and the receptor tyrosine kinase ErbB2 via the polarity protein, Par3, in Schwann cells. Binding of the neurotrophin BDNF to this complex activated ErbB2 signaling and in nerves from p75 deficient mice there was a reduction in ErbB2 activity. During normal development, signaling from receptor tyrosine kinases in Schwann cells activates lipid biogenesis and shuts down -oxidation to produce myelin. We propose that loss of the p75/ErbB2/Par3 complex disrupts cholesterol biosynthesis, leading to oxysterol production, and shifts lipids to -oxidation, which results in accumulation of acylcarnitines. We further hypothesize that the release of oxysterols and acylcarnitines by the Schwann cells causes degeneration of sensory neurons. In this project, we will test these hypotheses by a) defining the populations of neurons affected in mice lacking p75 in Schwann cells; b) determining whether the production of oxysterols and/or acylcarnitines by the glia accounts for the neuron loss; c) elucidating the mechanisms by which p75 regulates lipid metabolism. The results will reveal unique mechanisms by which Schwann cells modulate neuron viability, thereby providing new insights into the etiology of peripheral neuropathy.

周围神经病是一种令人衰弱的，通常与各种各样的痛苦疾病。不幸的是，在大多数情况下，没有针对神经变性的治疗方法，强调了需求更好地了解调节轴突完整性和神经元生存力的机制。一个关键调节器神经元的生存和轴突生长是神经营养蛋白的家族，它通过与TRK家族结合起作用受体酪氨酸激酶和p75神经营养蛋白受体。 TRK的激活促进生存和生长，而刺激p75可以诱导凋亡和轴突变性。但是，p75也可以形成与介导促生存信号传导的TRK的高亲和力复合物。降低神经营养蛋白信号传导神经元导致人类的感觉功能受损，而神经营养蛋白信号的完全丧失导致广泛的神经元细胞凋亡。例如，缺乏p75的小鼠在其背部失去了约50％的感觉神经元根神经节（DRG）是由于神经元中P75-TRK复合物的减少所致导致营养支持不足。但是，p75也在schwann细胞中表达，我们使令人惊讶的发现，Schwann细胞中P75的选择性缺失导致DRG降低了30％神经元和提高热敏感性。这些结果支持越来越多的证据表明神经胶质细胞至关重要神经元功能和活力的调节剂。我们还发现p75 - / - 神经中的脂质代谢改变了，神经毒性的氧化酚和酰基肉碱的明显增加。因此，我们假设p75 Null Schwann细胞释放这些脂质，导致神经变性。在考虑P75如何调节时脂质代谢，我们通过p75和受体酪氨酸激酶ERBB2通过 Schwann细胞中的极性蛋白，PAR3。神经营养蛋白BDNF与该复合物激活的ERBB2结合信号传导和p75缺乏小鼠的神经中的ERBB2活性降低。在正常情况下开发，来自雪旺细胞中受体酪氨酸激酶的信号传导激活脂质生物发生并关闭下氧化以产生髓磷脂。我们建议损失p75/erbb2/par3复合物破坏胆固醇生物合成，导致氧酚产生，并将脂质转移到氧化，从而导致积累酰基肉碱。我们进一步假设，雪旺氏细胞释放氧引起感觉神经元的变性。在这个项目中，我们将通过a）定义来检验这些假设在雪旺细胞中缺乏p75的小鼠中受影响的神经元群体； b）确定生产是否神经胶质的氧化酚和/或酰基肉碱造成神经元丧失； c）通过 P75调节脂质代谢。结果将揭示Schwann细胞的独特机制调节神经元的生存力，从而为周围神经病的病因提供新的见解。