Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury
Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury
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DOI：
10.1038/nn2000
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发表时间：
2007-11-01
影响因子：
25
通讯作者：
Nykjaer, Anders
中科院分区：
文献类型：
--
作者：
Jansen, Pernille;Giehl, Klaus;Nykjaer, Anders
神经营养因子对脊椎动物神经系统的发育和维持至关重要。有趣的是，虽然成熟的神经营养因子通过结合原肌球蛋白受体激酶和p75神经营养因子受体（p75（NTR））促进神经元存活，但前神经营养因子通过将分拣蛋白和p75（NTR）结合在死亡信号受体复合物中诱导培养的神经元凋亡。大量的神经营养因子在体内以前体形式分泌，但其生理意义仍不清楚。我们产生了一个分拣蛋白缺陷的小鼠来检查p75（NTR）/分拣蛋白受体复合物对神经元活力的贡献。在发育中的视网膜中，分拣蛋白1（Sort 1）（-/-）小鼠显示出减少的神经元凋亡，这与在p75（NTR）缺陷（Ngfr（-/-））小鼠中观察到的神经元凋亡难以区分。令我们惊讶的是，虽然分拣蛋白缺乏并不影响交感神经元的发育调控凋亡，但它确实阻止了它们的年龄依赖性变性。此外，在损伤方案中，Sort 1（-/-）小鼠中受损的皮质脊髓神经元免于死亡。因此，分拣蛋白途径在病理条件下的促神经营养因子诱导的凋亡信号传导中具有不同的作用，而且在神经元发育和衰老的特定阶段中也具有不同的作用。
Neurotrophins are essential for development and maintenance of the vertebrate nervous system. Paradoxically, although mature neurotrophins promote neuronal survival by binding to tropomyosin receptor kinases and p75 neurotrophin receptor (p75(NTR)), pro-neurotrophins induce apoptosis in cultured neurons by engaging sortilin and p75(NTR) in a death-signaling receptor complex. Substantial amounts of neurotrophins are secreted in pro-form in vivo, yet their physiological significance remains unclear. We generated a sortilin-deficient mouse to examine the contribution of the p75(NTR)/sortilin receptor complex to neuronal viability. In the developing retina, Sortilin 1 (Sort1)(-/-) mice showed reduced neuronal apoptosis that was indistinguishable from that observed in p75(NTR)-deficient (Ngfr(-/-)) mice. To our surprise, although sortilin deficiency did not affect developmentally regulated apoptosis of sympathetic neurons, it did prevent their age-dependent degeneration. Furthermore, in an injury protocol, lesioned corticospinal neurons in Sort1(-/-) mice were protected from death. Thus, the sortilin pathway has distinct roles in pro-neurotrophin-induced apoptotic signaling in pathological conditions, but also in specific stages of neuronal development and aging.