The Role of Netrin-1 in Improving Functional Recovery Through Autophagy Stimulation Following Spinal Cord Injury in Rats

Overview

Journal Front Cell Neurosci

Specialty Cell Biology

Date 2017 Dec 7

PMID 29209172

Citations 16

Authors

Liangjie Bai

Xifan Mei

Yanfeng Wang

Yajiang Yuan

Yunlong Bi

Gang Li

Hongyu Wang

Peng Yan

Gang Lv

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Bioinformatics analysis of genes associated with disulfidptosis in spinal cord injury.

Wang S, Liu X, Tian J, Liu S, Ke L, Zhang S PLoS One. 2025; 20(2):e0318016.

PMID: 39951434 PMC: 11828381. DOI: 10.1371/journal.pone.0318016.

Neuron-derived Netrin-1 deficiency aggravates spinal cord injury through activating the NF-κB signaling pathway.

Qin X, Zhang X, He X, Xu H, Yao Q, Li Z Heliyon. 2024; 10(17):e37388.

PMID: 39290272 PMC: 11407054. DOI: 10.1016/j.heliyon.2024.e37388.

Neuroprotective Effects of Oxymatrine via Triggering Autophagy and Inhibiting Apoptosis Following Spinal Cord Injury in Rats.

Li J, Cao Y, Li L, Chu X, Wang Y, Cai J Mol Neurobiol. 2023; 60(8):4450-4471.

PMID: 37115405 DOI: 10.1007/s12035-023-03364-1.

Netrin-1: A Serum Marker Predicting Cognitive Impairment after Spinal Cord Injury.

Meng Y, Sun S, Cao S, Shi B Dis Markers. 2022; 2022:1033197.

PMID: 35493300 PMC: 9050267. DOI: 10.1155/2022/1033197.

Restoration of ER proteostasis attenuates remote apoptotic cell death after spinal cord injury by reducing autophagosome overload.

Bisicchia E, Mastrantonio R, Nobili A, Palazzo C, La Barbera L, Latini L Cell Death Dis. 2022; 13(4):381.

PMID: 35444186 PMC: 9021197. DOI: 10.1038/s41419-022-04830-9.

References

Yang J, Liu X, Bhalla K, Kim C, Ibrado A, Cai J . Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science. 1997; 275(5303):1129-32. DOI: 10.1126/science.275.5303.1129. View

Sarkar S, Floto R, Berger Z, Imarisio S, Cordenier A, Pasco M . Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol. 2005; 170(7):1101-11. PMC: 2171537. DOI: 10.1083/jcb.200504035. View

Lai Wing Sun K, Correia J, Kennedy T . Netrins: versatile extracellular cues with diverse functions. Development. 2011; 138(11):2153-69. DOI: 10.1242/dev.044529. View

Warden P, Bamber N, Li H, Esposito A, Ahmad K, Hsu C . Delayed glial cell death following wallerian degeneration in white matter tracts after spinal cord dorsal column cordotomy in adult rats. Exp Neurol. 2001; 168(2):213-24. DOI: 10.1006/exnr.2000.7622. View

Ding Q, Liao S, Yu J . Axon guidance factor netrin-1 and its receptors regulate angiogenesis after cerebral ischemia. Neurosci Bull. 2014; 30(4):683-91. PMC: 5562620. DOI: 10.1007/s12264-013-1441-9. View

Roczniak-Ferguson A, Petit C, Froehlich F, Qian S, Ky J, Angarola B . The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012; 5(228):ra42. PMC: 3437338. DOI: 10.1126/scisignal.2002790. View

Mizushima N . Autophagy: process and function. Genes Dev. 2007; 21(22):2861-73. DOI: 10.1101/gad.1599207. View

Bethea J, Dietrich W . Targeting the host inflammatory response in traumatic spinal cord injury. Curr Opin Neurol. 2002; 15(3):355-60. DOI: 10.1097/00019052-200206000-00021. View

Settembre C, Zoncu R, Medina D, Vetrini F, Erdin S, Erdin S . A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012; 31(5):1095-108. PMC: 3298007. DOI: 10.1038/emboj.2012.32. View

10.

Medina D, Settembre C, Ballabio A . Methods to Monitor and Manipulate TFEB Activity During Autophagy. Methods Enzymol. 2017; 588:61-78. DOI: 10.1016/bs.mie.2016.10.008. View

11.

Li H, Zhao X, Zhang X, Li G, Jia Z, Sun P . Exendin-4 Enhances Motor Function Recovery via Promotion of Autophagy and Inhibition of Neuronal Apoptosis After Spinal Cord Injury in Rats. Mol Neurobiol. 2015; 53(6):4073-4082. DOI: 10.1007/s12035-015-9327-7. View

12.

Shin H, Kim H, Oh S, Lee J, Kee M, Ko H . AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature. 2016; 534(7608):553-7. PMC: 5568428. DOI: 10.1038/nature18014. View

13.

Dasgupta B, Milbrandt J . Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A. 2007; 104(17):7217-22. PMC: 1855377. DOI: 10.1073/pnas.0610068104. View

14.

Penas C, Guzman M, Verdu E, Fores J, Navarro X, Casas C . Spinal cord injury induces endoplasmic reticulum stress with different cell-type dependent response. J Neurochem. 2007; 102(4):1242-55. DOI: 10.1111/j.1471-4159.2007.04671.x. View

15.

Settembre C, Fraldi A, Medina D, Ballabio A . Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol. 2013; 14(5):283-96. PMC: 4387238. DOI: 10.1038/nrm3565. View

16.

Min J, Huo X, Xiang L, Qin Y, Chai K, Wu B . Protective effect of Dl-3n-butylphthalide on learning and memory impairment induced by chronic intermittent hypoxia-hypercapnia exposure. Sci Rep. 2014; 4:5555. PMC: 4080197. DOI: 10.1038/srep05555. View

17.

Wei M, Zong W, Cheng E, LINDSTEN T, Panoutsakopoulou V, Ross A . Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001; 292(5517):727-30. PMC: 3049805. DOI: 10.1126/science.1059108. View

18.

Gwinn D, Shackelford D, Egan D, Mihaylova M, Mery A, Vasquez D . AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008; 30(2):214-26. PMC: 2674027. DOI: 10.1016/j.molcel.2008.03.003. View

19.

Rehli M, den Elzen N, Cassady A, Ostrowski M, Hume D . Cloning and characterization of the murine genes for bHLH-ZIP transcription factors TFEC and TFEB reveal a common gene organization for all MiT subfamily members. Genomics. 1999; 56(1):111-20. DOI: 10.1006/geno.1998.5588. View

20.

Bove J, Martinez-Vicente M, Vila M . Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci. 2011; 12(8):437-52. DOI: 10.1038/nrn3068. View