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

周围神经病是一种衰弱且通常令人痛苦的疾病，与多种 疾病。不幸的是，在大多数情况下，没有治疗神经退行性变的方法，这突出了需要 以更好地了解调节轴突完整性和神经元活性的机制。一个关键的监管机构 神经元存活和轴突生长是神经营养因子家族，它通过与Trk家族结合发挥作用。 受体酪氨酸激酶和p75神经营养素受体。Trks的激活促进了生存和 刺激p75可诱导细胞凋亡和轴突变性。然而，p75也可以形成一种 与Trks的高亲和力复合体，介导支持生存的信号。神经营养因子信号转导减少 神经元导致人类感觉功能受损，神经营养素信号完全丧失导致 广泛的神经细胞凋亡。例如，缺乏p75的小鼠背部失去了~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复合体的减少， 导致营养支持不足。然而，p75也在雪旺细胞中表达，我们制作了 令人惊讶的发现，雪旺细胞中p75的选择性缺失导致DRG减少30% 神经元和热敏感度降低。这些结果支持了越来越多的证据，即神经胶质细胞是至关重要的 神经功能和生存能力的调节剂。我们还发现p75-/-神经中的脂质代谢发生了变化， 氧类固醇和酰肉碱的显著增加，这两种物质具有神经毒性。因此，我们假设p75 零雪旺细胞释放这些脂类，导致神经退化。在考虑p75如何调节 脂代谢，我们发现了p75和受体酪氨酸激酶ErbB2之间的一个新的复合体，它通过 雪旺细胞中的极性蛋白Par3。神经营养因子BDNF与该复合物激活的ErbB2的结合 在p75基因缺陷的小鼠的神经中，ErbB2活性降低。在正常期间 雪旺细胞受体酪氨酸激酶信号的发育激活脂质生物生成和关闭 向下-氧化产生髓磷脂。我们认为p75/ErbB2/Par3复合体的缺失会破坏胆固醇 生物合成，导致氧固醇的产生，并将脂肪转化为氧化，从而导致积累 酰基卡尼汀。我们进一步假设，雪旺细胞释放氧固醇和酰肉碱 会导致感觉神经元退化。在本项目中，我们将通过a)定义 雪旺细胞中缺乏p75的小鼠受影响的神经元群体；b)确定是否产生 胶质细胞产生的氧固醇和/或酰肉碱是神经元丢失的原因；c)通过以下方式阐明其机制 其中p75调节脂类代谢。这一结果将揭示雪旺细胞 调节神经元活性，从而为周围神经病的病因学提供新的见解。

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.