The Role of Netrin-1 in Improving Functional Recovery through Autophagy Stimulation Following Spinal Cord Injury in Rats.
The Role of Netrin-1 in Improving Functional Recovery through Autophagy Stimulation Following Spinal Cord Injury in Rats.
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Netrin-1 在大鼠脊髓损伤后通过自噬刺激改善功能恢复的作用。
DOI：
10.3389/fncel.2017.00350
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发表时间：
2017
影响因子：
5.3
通讯作者：
Lv G
中科院分区：
文献类型：
--
作者：
Bai L;Mei X;Wang Y;Yuan Y;Bi Y;Li G;Wang H;Yan P;Lv G
我们以前的研究结果表明，Netrin-1可以通过激活AMP激活的蛋白激酶/哺乳动物雷帕霉素靶点(AMPK/mTOR)信号通路，促进脊髓损伤(SCI)后大鼠的功能恢复。然而，其潜在的机制尚未阐明。本研究的目的是探讨Netrin-1促进脊髓损伤后自噬和促进功能恢复的潜在机制。在SD大鼠控制脊髓损伤后，我们观察到神经元的自噬通量受到损害，表现为轻链3-II(Lc3-II)阳性和Lc3阳性的自噬小体(AP)的积累，并伴随着自噬底物Sequestosome 1(SQSTM1；也称为p62)的积累。我们的结果表明，Netrin-1通过AMPK/mTOR信号通路调节转录因子EB(TFEB)的核定位，从而增加溶酶体蛋白水解酶组织蛋白D(CTSD)和溶酶体相关膜蛋白1(LAMP1)的水平。此外，溶酶体生物合成的这种增强与自噬通量的恢复、抑制神经细胞凋亡和改善功能恢复密切相关。化合物C通过抑制TFEB的核转位来抑制溶酶体的生物发生，从而取消了自噬通量的恢复和脊髓损伤后Netrin-1的功能恢复效应。综上所述，这些结果表明，Netrin-1通过AMPK/mTOR信号通路调节TFEB的核转位，从而促进溶酶体的生物发生。此外，脊髓损伤后Netrin-1促进溶酶体的生物合成，促进自噬通量，促进大鼠功能恢复。因此，通过调控TFEB的核定位来调控溶酶体的生物发生可能是治疗脊髓损伤的新途径。
Our previous findings indicated that treatment with Netrin-1 could improve functional recovery through the stimulation of autophagy, by activating the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway in rats following spinal cord injury (SCI). However, the underlying mechanisms were not elucidated. The purpose of this study was to investigate the underlying mechanisms by which Netrin-1 promotes autophagy and improves functional recovery after SCI. Following controlled SCI in Sprague-Dawley rats, we observed that the autophagic flux in neurons was impaired, as reflected by the accumulation of light chain 3-II (LC3-II)-positive and LC3-positive autophagosomes (APs), accompanied by the accumulation of the autophagic substrate, Sequestosome 1 (SQSTM1; also known as p62). Our results showed that treatment with Netrin-1 increases the levels of the lysosomal protease cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1), through the regulation of the nuclear localization of Transcription factor EB (TFEB) via the AMPK/mTOR signaling pathway. In addition, this enhancement of lysosomal biogenesis correlated strongly with the restoration of autophagic flux, inhibition of neural apoptosis and improved functional recovery. Suppression of lysosomal biogenesis via the inhibition of the nuclear translocation of TFEB by Compound C abolished this restoration of autophagic flux and the functional recovery effects of Netrin-1 following SCI. Taken together, these results indicate that Netrin-1 enhances lysosomal biogenesis by regulating the nuclear translocation of TFEB via the AMPK/mTOR signaling pathway. Furthermore, the enhancement of lysosomal biogenesis by Netrin-1 following SCI promotes autophagic flux and improves functional recovery in rats. Thus, the regulation of lysosomal biogenesis by modulating the nuclear localization of TFEB might be a novel approach for the treatment of SCI.
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影响因子：
6.1
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
11.1
作者：
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影响因子：
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