The neunte outgrowth inhibitor A (Nogo-A) is a protein found in mammals, which is capable of inhibiting axon growth. Previous research has found that Nogo-A can play a regulatory role in axon growth and synaptic plasticity in the nervous system, and it is closely associated with Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and spinal cord injuries. This article reviewed the basic structure and functions of Nogo-A and its receptor NgR, as well as the research progress in the context of neurological disorders.

1.Schmandke A, Schmandke A, Schwab ME. Nogo-A: multiple roles in CNS development, maintenance, and disease[J]. Neuroscientist, 2014, 20(4): 372-386. DOI: 10.1177/1073858413516800.

2.Long SL, Li YK, Xie YJ, et al. Neurite outgrowth inhibitor B receptor: a versatile receptor with multiple functions and actions[J]. DNA Cell Biol, 2017, 36(12): 1142-1150. DOI: 10.1089/dna.2017.3813.

3.Kulczyńska-Przybik A, Mroczko P, Dulewicz M, et al. The implication of reticulons (RTNs) in neurodegenerative diseases: from molecular mechanisms to potential diagnostic and therapeutic approaches[J]. Int J Mol Sci, 2021, 22(9): 4630. DOI: 10.3390/ijms22094630.

4.Zelenay V, Arzt ME, Bibow S, et al. The neurite outgrowth inhibitory Nogo-A-Δ20 region is an intrinsically disordered segment harbouring three stretches with helical propensity[J]. PLoS One, 2016, 11(9): e0161813. DOI: 10.1371/journal.pone.0161813.

5.Huber AB, Weinmann O, Brösamle C, et al. Patterns of Nogo mRNA and protein expression in the developing and adult rat and after CNS lesions[J]. J Neurosci, 2002, 22(9): 3553-3567. DOI: 10.1523/JNEUROSCI.22-09-03553.2002.

6.Seiler S, Di Santo S, Widmer HR. Non-canonical actions of Nogo-A and its receptors[J]. Biochem Pharmacol, 2016, 100: 28-39. DOI: 10.1016/j.bcp.2015.08.113.

7.Smedfors G, Olson L, Karlsson TE. A Nogo-Like signaling perspective from birth to adulthood and in old age: brain expression patterns of ligands, receptors and modulators[J]. Front Mol Neurosci, 2018, 11: 42. DOI: 10.3389/fnmol. 2018.00042.

8.Karlsson TE, Wellfelt K, Olson L. Spatiotemporal and long lasting modulation of 11 key Nogo signaling genes in response to strong neuroexcitation[J]. Front Mol Neurosci, 2017, 10: 94. DOI: 10.3389/fnmol.2017.00094.

9.Petrinovic MM, Duncan CS, Bourikas D, et al. Neuronal Nogo-A regulates neurite fasciculation, branching and extension in the developing nervous system[J]. Development, 2010, 137(15): 2539-2550. DOI: 10.1242/dev.048371.

10.Schmandke A, Mosberger AC, Schmandke A, et al. The neurite growth inhibitory protein Nogo-A has diverse roles in adhesion and migration[J]. Cell Adh Migr, 2013, 7(6): 451-454. DOI: 10.4161/cam.27164.

11.Kempf A, Schwab ME. Nogo-A represses anatomical and synaptic plasticity in the central nervous system[J]. Physiology (Bethesda), 2013, 28(3): 151-163. DOI: 10.1152/physiol.00052.2012.

12.Pernet V, Schwab ME. The role of Nogo-A in axonal plasticity, regrowth and repair[J]. Cell Tissue Res, 2012, 349(1): 97-104. DOI: 10.1007/s00441-012-1432-6.

13.Zemmar A, Weinmann O, Kellner Y, et al. Neutralization of Nogo-A enhances synaptic plasticity in the rodent motor cortex and improves motor learning in vivo[J]. J Neurosci, 2014, 34(26): 8685-8698. DOI: 10.1523/JNEUROSCI.3817-13.2014.

14.Tiwari S, Atluri V, Kaushik A, et al. Alzheimer's disease: pathogenesis, diagnostics, and therapeutics[J]. Int J Nanomedicine, 2019, 14: 5541-5554. DOI: 10.2147/IJN.S200490.

15.Xie QQ, Feng X, Huang YY, et al. Nogo-66 promotes β-amyloid protein secretion via NgR/ROCK-dependent BACE1 activation[J]. Mol Med Rep, 2021, 23(3): 188. DOI: 10.3892/mmr.2021.11827.

16.Wang J, Qin X, Sun H, et al. Nogo receptor impairs the clearance of fibril amyloid-β by microglia and accelerates Alzheimer's-like disease progression[J]. Aging Cell, 2021, 20(12): e13515. DOI: 10.1111/acel.13515.

17.Jiang R, Wu XF, Wang B, et al. Reduction of NgR in perforant path decreases amyloid-β peptide production and ameliorates synaptic and cognitive deficits in APP/PS1 mice[J]. Alzheimers Res Ther, 2020, 12(1): 47. DOI: 10.1186/s13195-020-00616-3.

18.Pavon MV, Navakkode S, Wong LW, et al. Inhibition of Nogo-A rescues synaptic plasticity and associativity in APP/PS1 animal model of Alzheimer's disease[J]. Semin Cell Dev Biol, 2023, 139: 111-120. DOI: 10.1016/j.semcdb.2022.04.005.

19.Gumus H, Baltaci SB, Unal O, et al. Zinc ameliorates Nogo-A receptor and osteocalcin gene expression in memory-sensitive rat hippocampus impaired by intracerebroventricular injection of streptozotocin[J]. Biol Trace Elem Res, 2023, 201(7): 3381-3386. DOI: 10.1007/s12011-022-03410-4.

20.Mead RJ, Shan N, Reiser HJ, et al. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation[J]. Nat Rev Drug Discov, 2023, 22(3): 185-212. DOI: 10.1038/s41573-022-00612-2.  

21.Calvo AC, Manzano R, Mendonça DM, et al. Amyotrophic lateral sclerosis: a focus on disease progression[J]. Biomed Res Int, 2014, 2014: 925101. DOI: 10.1155/2014/925101.

22.Park S, Park JH, Kang UB, et al. Nogo-A regulates myogenesis via interacting with Filamin-C[J]. Cell Death Discov, 2021, 7(1): 1. DOI: 10.1038/s41420-020-00384-x.

23.Ullah HMA, Elfadl AK, Park S, et al. Nogo-A is critical for pro-inflammatory gene regulation in myocytes and macrophages[J]. Cells, 2021, 10(2): 282. DOI: 10.3390/cells10020282.

24.Meininger V, Genge A, van den Berg LH, et al. Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial[J]. Lancet Neurol, 2017, 16(3): 208-216. DOI: 10.1016/S1474-4422(16)30399-4.

25.Shah A, Panchal V, Patel K, et al. Pathogenesis and management of multiple sclerosis revisited[J]. Dis Mon, 2023, 69(9): 101497. DOI: 10.1016/j.disamonth. 2022.101497.

26.Pradhan LK, Das SK. The regulatory role of reticulons in neurodegeneration: insights underpinning therapeutic potential for neurodegenerative diseases[J]. Cell Mol Neurobiol, 2021, 41(6): 1157-1174. DOI: 10.1007/s10571-020-00893-4.

27.Karnezis T, Mandemakers W, McQualter JL, et al. The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination[J]. Nat Neurosci, 2004, 7(7): 736-744. DOI: 10.1038/nn1261.

28.Ineichen BV, Kapitza S, Bleul C, et al. Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology[J]. Acta Neuropathol, 2017, 134(3): 423-440. DOI: 10.1007/s00401-017-1745-3.

29.Lee JY, Kim MJ, Li L, et al. Nogo receptor 1 regulates Caspr distribution at axo-glial units in the central nervous system[J]. Sci Rep, 2017, 7(1): 8958. DOI: 10.1038/s41598-017-09405-9.

30.Tu WJ, Wang LD, Special Writing Group of China Stroke Surveillance Report. China stroke surveillance report 2021[J]. Mil Med Res, 2023, 10(1): 33. DOI: 10.1186/s40779-023-00463-x.

31.Orfila JE, Dietz RM, Rodgers KM, et al. Experimental pediatric stroke shows age-specific recovery of cognition and role of hippocampal Nogo-A receptor signaling[J]. J Cereb Blood Flow Metab, 2020, 40(3): 588-599. DOI: 10.1177/0271678X19828581.

32.Rust R, Grönnert L, Gantner C, et al. Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke[J]. Proc Natl Acad Sci USA, 2019, 116(28): 14270-14279. DOI: 10.1073/pnas.1905309116.

33.Rust R, Holm MM, Egger M, et al. Nogo-A is secreted in extracellular vesicles, occurs in blood and can influence vascular permeability[J/OL]. J Cereb Blood Flow Metab, 2023. [2023-11-04]. DOI: 10.1177/0271678X231216270.

34.Xu W, Xiao P, Fan S, et al. Blockade of Nogo-A/Nogo-66 receptor 1 (NgR1) inhibits autophagic activation and prevents secondary neuronal damage in the thalamus after focal cerebral infarction in hypertensive rats[J]. Neuroscience, 2020, 431: 103-114. DOI: 10.1016/j.neuroscience.2020.02.010.

35.Xiao P, Gu J, Xu W, et al. RTN4/Nogo-A-S1PR2 negatively regulates angiogenesis and secondary neural repair through enhancing vascular autophagy in the thalamus after cerebral cortical infarction[J]. Autophagy, 2022, 18(11): 2711-2730. DOI: 10.1080/15548627. 2022.2047344.

36.Rust R, Weber RZ, Grönnert L, et al. Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke[J]. Sci Rep, 2019, 9(1): 20040. DOI: 10.1038/s41598-019-56634-1.

37.Eli I, Lerner DP, Ghogawala Z. Acute traumatic spinal cord injury[J]. Neurol Clin, 2021, 39(2): 471-488. DOI: 10.1016/j.ncl.2021.02.004.

38.Schnell L, Schwab ME. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors[J]. Nature, 1990, 343(6255): 269-272. DOI: 10.1038/343269a0.

39.Wang JW, Yang JF, Ma Y, et al. Nogo-A expression dynamically varies after spinal cord injury[J]. Neural Regen Res, 2015, 10(2): 225-229. DOI: 10.4103/1673-5374.152375.

40.Shi H, Xie L, Xu W, et al. Nogo-A is a potential prognostic marker for spinal cord injury[J]. Dis Markers, 2022, 2022: 2141854. DOI: 10.1155/2022/2141854.

41.Hirt J, Khanteymoori A, Hohenhaus M, et al. Inhibition of the Nogo-pathway in experimental spinal cord injury: a meta-analysis of 76 experimental treatments[J]. Sci Rep, 2023, 13(1): 22898. DOI: 10.1038/s41598-023-49260-5.

42.Beaud ML, Rouiller EM, Bloch J, et al. Combined with anti-Nogo-A antibody treatment, BDNF did not compensate the extra deleterious motor effect caused by large size cervical cord hemisection in adult macaques[J]. CNS Neurosci Ther, 2020, 26(2): 260-269. DOI: 10.1111/cns.13213.