Lady Davis Institute-Jewish General Hospital, McGill University, Montréal, QC, H3T 1E2, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
Cell Death Dis. 2017 Dec 14;8(12):3222. doi: 10.1038/s41419-017-0074-8.
In some diseases the TrkC.T1 isoform is upregulated in glia, associated with glial TNF-α production and neuronal death. What remains unknown are the activating signals in glia, and how paracrine signals may be selective for a targeted neuron while sparing other proximate neurons. We studied these questions in the retina, where Müller glia contacts photoreceptors on one side and retinal ganglion cells on the other. In a mutant Rhodopsin mouse model of retinitis pigmentosa (RP) causing progressive photoreceptor death-but sparing retinal ganglion cells-TrkC.T1 and NT-3 ligand are upregulated in Müller glia. TrkC.T1 activity generates p-Erk, which causes increased TNF-α. These sequential events take place predominantly in Müller fibers contacting stressed photoreceptors, and culminate in selective death. Each event and photoreceptor death can be prevented by reduction of TrkC.T1 expression, by pharmacological antagonism of TrkC or by pharmacological inhibition Erk. Unmasking the sequence of non-cell autologous events and mechanisms causing selective neuronal death may help rationalize therapies.
在某些疾病中，TrkC.T1 同工型在神经胶质细胞中上调，与神经胶质细胞 TNF-α 的产生和神经元死亡有关。目前尚不清楚的是神经胶质细胞中的激活信号，以及旁分泌信号如何选择性地针对特定神经元，而不影响其他邻近神经元。我们在视网膜中研究了这些问题，在视网膜中，Müller 胶质细胞的一侧与光感受器接触，另一侧与视网膜神经节细胞接触。在一种导致光感受器进行性死亡但保留视网膜神经节细胞的致 RP 突变视紫红质小鼠模型中，TrkC.T1 和 NT-3 配体在 Müller 胶质细胞中上调。TrkC.T1 活性产生 p-Erk，导致 TNF-α 的增加。这些连续的事件主要发生在与受应激光感受器接触的 Müller 纤维中，并导致选择性死亡。通过降低 TrkC.T1 的表达、药理学拮抗 TrkC 或药理学抑制 Erk，可以预防每个事件和光感受器死亡。揭示导致选择性神经元死亡的非细胞自体同源事件和机制的顺序可能有助于合理化治疗。
