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首页> 外文期刊>The European Journal of Neuroscience >Proneurotrophin-3 may induce Sortilin-dependent death in inner ear neurons.
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Proneurotrophin-3 may induce Sortilin-dependent death in inner ear neurons.

机译：前神经营养蛋白3可能诱导内耳神经元的Sortilin依赖性死亡。

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摘要

The precursor of the neurotrophin (NT) nerve growth factor (NGF) (proNGF) serves physiological functions distinct from its mature counterpart as it induces neuronal apoptosis through activation of a p75 NT receptor (p75(NTR) ) and Sortilin death-signalling complex. The NTs brain-derived nerve growth factor (BDNF) and NT3 provide essential trophic support to auditory neurons. Injury to the NT-secreting cells in the inner ear is followed by irreversible degeneration of spiral ganglion neurons with consequences such as impaired hearing or deafness. Lack of mature NTs may explain the degeneration of spiral ganglion neurons, but another mechanism is possible as unprocessed proNTs released from the injured cells may contribute to the degeneration by induction of apoptosis. Recent studies demonstrate that proBDNF, like proNGF, is a potent inducer of Sortilin:p75(NTR) -mediated apoptosis. In addition, a coincident upregulation of proBDNF and p75(NTR) has been observed in degenerating spiral ganglion neurons, but the Sortilin expression in the inner ear is unresolved. Here we demonstrate that Sortilin and p75(NTR) are coexpressed in neurons of the neonatal inner ear. Furthermore, we establish that proNT3 exhibits high-affinity binding to Sortilin and has the capacity to enhance cell surface Sortilin:p75(NTR) complex formation as well as to mediate apoptosis in neurons coexpressing p75(NTR) and Sortilin. Based on the examination of wildtype and Sortilin-deficient mouse embryos, Sortilin does not significantly influence the developmental selection of spiral ganglion neurons. However, our results suggest that proNT3 and proBDNF may play important roles in the response to noise-induced injuries or ototoxic damage via the Sortilin:p75(NTR) death-signalling complex.
机译：神经营养蛋白（NT）神经生长因子（NGF）（proNGF）的前体具有与其成熟对应物不同的生理功能，因为它通过激活p75 NT受体（p75（NTR））和Sortilin死亡信号复合物诱导神经元凋亡。 NTs的脑源性神经生长因子（BDNF）和NT3为听神经元提供了必需的营养支持。内耳NT分泌细胞受伤后，螺旋神经节神经元发生不可逆的变性，其后果是听力受损或耳聋。缺乏成熟的NT可能解释了螺旋神经节神经元的退化，但是另一种机制是可能的，因为从受损细胞释放的未加工的proNT可能通过诱导细胞凋亡而导致退化。最近的研究表明，proBDNF与proNGF一样，是Sortilin：p75（NTR）介导的细胞凋亡的有效诱导剂。此外，在退化的螺旋神经节神经元中观察到了proBDNF和p75（NTR）的同时上调，但是内耳中的Sortilin表达仍未得到解决。在这里，我们证明Sortilin和p75（NTR）在新生儿内耳的神经元中共表达。此外，我们确定proNT3表现出与Sortilin的高亲和力结合，并具有增强细胞表面Sortilin：p75（NTR）复合物形成的能力，以及介导共表达p75（NTR）和Sortilin的神经元凋亡的能力。根据对野生型和Sortilin缺陷型小鼠胚胎的检查，Sortilin不会显着影响螺旋神经节神经元的发育选择。但是，我们的研究结果表明，proNT3和proBDNF可能在通过Sortilin：p75（NTR）死亡信号复合物应答噪声引起的损伤或耳毒性损伤中发挥重要作用。

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