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

• 批准号: 10170449
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170449
• 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; 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

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.

周围神经病变是一种使人衰弱且通常疼痛的病症，其与各种各样的神经病变相关。 疾病不幸的是，在大多数情况下，神经退行性疾病没有治疗方法，这凸显了这种需要 以更好地理解调节轴突完整性和神经元活力的机制。一个关键的监管机构， 神经元存活和轴突生长是神经营养蛋白家族，其通过结合到Trk家族， 受体酪氨酸激酶和p75神经营养因子受体。Trks的激活促进存活， 而p75的刺激可诱导细胞凋亡和轴突变性。p75也可以形成 与介导促存活信号传导的Trks形成高亲和力复合物。减少神经营养素信号传导 神经元导致人类感觉功能受损，神经营养蛋白信号传导的完全丧失导致 广泛的神经元凋亡。例如，缺乏p75的小鼠在其背侧失去了约50%的感觉神经元。 根神经节（DRG），这被认为是由于神经元中p75-Trk复合物的减少， 导致营养支持不足。然而，p75也在雪旺细胞中表达，我们制备了 一个令人惊讶的发现，在雪旺细胞中选择性缺失p75导致DRG减少30 神经元和热敏感性降低。这些结果支持越来越多的证据表明，神经胶质细胞是至关重要的 调节神经元功能和活力。我们还发现p75-/-神经的脂质代谢改变， 氧化固醇和酰基肉毒碱显著增加，这是神经毒性。因此，我们假设p75 无效的雪旺氏细胞释放这些脂质，导致神经变性。在考虑p75如何调节 脂质代谢，我们确定了一种新的复合物p75和受体酪氨酸激酶ErbB 2通过 极性蛋白Par 3。神经营养因子BDNF与该复合物的结合激活了ErbB 2 在p75缺陷小鼠的神经中，ErbB 2活性降低。在正常 在发育过程中，来自雪旺细胞中受体酪氨酸激酶的信号激活脂质生物合成并关闭 降低β-氧化产生髓磷脂。我们认为p75/ErbB 2/Par 3复合物的丢失破坏了胆固醇 生物合成，导致氧化固醇的产生，并将脂质转化为β-氧化，这导致 酰基肉毒碱我们进一步假设许旺细胞释放氧固醇和酰基肉毒碱 导致感觉神经元退化在这个项目中，我们将通过a）定义 在雪旺细胞中缺乏p75的小鼠中受影响的神经元群体; B）确定在雪旺细胞中p75的产生是否与神经元的产生有关。 神经胶质的氧化固醇和/或酰基肉毒碱解释了神经元损失; c）通过 其中p75调节脂质代谢。研究结果将揭示雪旺细胞 调节神经元的活力，从而为周围神经病变的病因学提供新的见解。