Neuronal pentraxin 2 (NP2) plays a significant role in synaptic plasticity, neuronal survival, and excitatory synapse regulation. Emerging research suggests that NP2 is implicated in the pathogenesis of various neurological disorders, including neurodegenerative diseases, neuropsychiatric disorders, and neuropathies. This literature review extensively analyzes NP2's role in these conditions, thereby highlighting its contributions to synaptic dysfunction, neuroinflammation, and neurotoxic protein aggregation. In Alzheimer's and Parkinson's diseases, NP2 is linked to amyloid-beta aggregation and dopaminergic neuron degeneration, respectively. Additionally, altered NP2 expression is observed in schizophrenia and bipolar disorder, thus suggesting its involvement in synaptic dysfunction and neurotransmitter imbalance. In neuropathic pain and epilepsy, NP2 modulates the synaptic plasticity and inflammatory responses, with altered levels correlating with disease severity. Furthermore, NP2's involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) emphasizes its broad impact on neuronal health. Understanding NP2's multifaceted roles may reveal novel therapeutic targets and improve the clinical outcomes for these neurological disorders. Though the precise role of NP2 remains uncertain, its clinical potential and initial findings justify further investigations into neuronal pentraxins and other related neuroproteins.
Citation: Ubaid Ansari, Jimmy Wen, Burhaan Syed, Dawnica Nadora, Romteen Sedighi, Denise Nadora, Vincent Chen, Forshing Lui. Analyzing the potential of neuronal pentraxin 2 as a biomarker in neurological disorders: A literature review[J]. AIMS Neuroscience, 2024, 11(4): 505-519. doi: 10.3934/Neuroscience.2024031
Neuronal pentraxin 2 (NP2) plays a significant role in synaptic plasticity, neuronal survival, and excitatory synapse regulation. Emerging research suggests that NP2 is implicated in the pathogenesis of various neurological disorders, including neurodegenerative diseases, neuropsychiatric disorders, and neuropathies. This literature review extensively analyzes NP2's role in these conditions, thereby highlighting its contributions to synaptic dysfunction, neuroinflammation, and neurotoxic protein aggregation. In Alzheimer's and Parkinson's diseases, NP2 is linked to amyloid-beta aggregation and dopaminergic neuron degeneration, respectively. Additionally, altered NP2 expression is observed in schizophrenia and bipolar disorder, thus suggesting its involvement in synaptic dysfunction and neurotransmitter imbalance. In neuropathic pain and epilepsy, NP2 modulates the synaptic plasticity and inflammatory responses, with altered levels correlating with disease severity. Furthermore, NP2's involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) emphasizes its broad impact on neuronal health. Understanding NP2's multifaceted roles may reveal novel therapeutic targets and improve the clinical outcomes for these neurological disorders. Though the precise role of NP2 remains uncertain, its clinical potential and initial findings justify further investigations into neuronal pentraxins and other related neuroproteins.
[1] | Borsook D (2012) Neurological diseases and pain. Brain 135: 320-344. https://doi.org/10.1093/brain/awr271 |
[2] | Chapman G, Shanmugalingam U, Smith PD (2020) The role of neuronal pentraxin 2 (NP2) in regulating glutamatergic signaling and neuropathology. Front Cell Neurosci 13. https://doi.org/10.3389/fncel.2019.00575 |
[3] | Xiao MF, Xu D, Craig MT, et al. (2017) NPTX2 and cognitive dysfunction in Alzheimer's Disease. Elife 6. https://doi.org/10.7554/eLife.23798 |
[4] | Moran LB, Hickey L, Michael GJ, et al. (2008) Neuronal pentraxin II is highly upregulated in Parkinson's disease and a novel component of Lewy bodies. Acta Neuropathol 115: 471-478. https://doi.org/10.1007/s00401-007-0309-3 |
[5] | Zhou J, Li X, Wang X, et al. (2024) Levels of neuronal pentraxin 2 in plasma is associated with cognitive function in patients with schizophrenia. Psychopharmacology 241: 865-874. https://doi.org/10.1007/s00213-023-06515-3 |
[6] | Wang R, Man Y, Zhou M, et al. (2021) Neuropathic pain-induced cognitive dysfunction and down-regulation of neuronal pentraxin 2 in the cortex and hippocampus. Neuroreport 32: 274-283. https://doi.org/10.1097/WNR.0000000000001584 |
[7] | Huang XF, Xu MX, Chen YF, et al. (2023) Serum neuronal pentraxin 2 is related to cognitive dysfunction and electroencephalogram slow wave/fast wave frequency ratio in epilepsy. World J Psychiatry 13: 714-723. https://doi.org/10.5498/wjp.v13.i10.714 |
[8] | Hruska-Plochan M, Wiersma VI, Betz KM, et al. (2024) A model of human neural networks reveals NPTX2 pathology in ALS and FTLD. Nature 626: 1073-1083. https://doi.org/10.1038/s41586-024-07042-7 |
[9] | Zhou J, Wade SD, Graykowski D, et al. (2023) The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration. Sci Transl Med 15: eadf0141. https://doi.org/10.1126/scitranslmed.adf0141 |
[10] | Xiao MF, Roh SE, Zhou J, et al. (2021) A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function. Sci Adv 7. https://doi.org/10.1126/sciadv.abf6935 |
[11] | Lee SJ, Wei M, Zhang C, et al. (2017) Presynaptic neuronal pentraxin receptor organizes excitatory and inhibitory synapses. J Neurosci 37: 1062-1080. https://doi.org/10.1523/JNEUROSCI.2768-16.2016 |
[12] | Sia GM, Béïque JC, Rumbaugh G, et al. (2007) Interaction of the N-terminal domain of the AMPA receptor GluR4 subunit with the neuronal pentraxin NP1 mediates GluR4 synaptic recruitment. Neuron 55: 87-102. https://doi.org/10.1016/j.neuron.2007.06.020 |
[13] | Cho RW, Park JM, Wolff SBE, et al. (2008) MGluR1/5-dependent long-term depression requires the regulated ectodomain cleavage of neuronal pentraxin NPR by TACE. Neuron 57: 858-871. https://doi.org/10.1016/j.neuron.2008.01.010 |
[14] | Ramana KV (2010) Tumor necrosis factor-alpha converting enzyme: Implications for ocular inflammatory diseases. Int J Biochem Cell Biol 42: 1076-1079. https://doi.org/10.1016/j.biocel.2010.03.011 |
[15] | Mariga A, Glaser J, Mathias L, et al. (2015) Definition of a bidirectional activity-dependent pathway involving BDNF and narp. Cell Rep 13: 1747-1756. https://doi.org/10.1016/j.celrep.2015.10.064 |
[16] | Fan L, Mao C, Hu X, et al. (2020) New insights into the pathogenesis of Alzheimer's disease. Front Neurol 10. https://doi.org/10.3389/fneur.2019.01312 |
[17] | Tiwari S, Atluri V, Kaushik A, et al. (2019) Alzheimer's disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomedicine 14: 5541-5554. https://doi.org/10.2147/IJN.S200490 |
[18] | Heneka MT, Carson MJ, Khoury JE, et al. (2015) Neuroinflammation in Alzheimer's disease. Lancet Neurol 14: 388-405. https://doi.org/10.1016/S1474-4422(15)70016-5 |
[19] | Meftah S, Gan J (2023) Alzheimer's disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression. Front Synaptic Neurosci 15. https://doi.org/10.3389/fnsyn.2023.1129036 |
[20] | Sheng M, Sabatini BL, Sudhof TC (2012) Synapses and Alzheimer's disease. Cold Spring Harb Perspect Biol 4: a005777-a005777. https://doi.org/10.1101/cshperspect.a005777 |
[21] | Swerdlow RH (2018) Mitochondria and Mitochondrial Cascades in Alzheimer's Disease. J Alzheimers Dis 62: 1403-1416. https://doi.org/10.3233/JAD-170585 |
[22] | Wang Z, Wang X, Zou H, et al. (2020) The basic characteristics of the pentraxin family and their functions in tumor progression. Front Immunol 11. https://doi.org/10.3389/fimmu.2020.01757 |
[23] | Kanehisa K, Koga K, Maejima S, et al. (2022) Neuronal pentraxin 2 is required for facilitating excitatory synaptic inputs onto spinal neurons involved in pruriceptive transmission in a model of chronic itch. Nat Commun 13: 1-11. https://doi.org/10.1038/s41467-022-30089-x |
[24] | Libiger O, Shaw LM, Watson MH, et al. (2021) Longitudinal CSF proteomics identifies NPTX2 as a prognostic biomarker of Alzheimer's disease. Alzheimers Dement 17: 1976-1987. https://doi.org/10.1002/alz.12353 |
[25] | Gómez de San José N, Massa F, Halbgebauer S, et al. (2022) Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration. J Neural Transm (Vienna) 129: 207-230. https://doi.org/10.1007/s00702-021-02411-2 |
[26] | Dulewicz M, Kulczyńska-Przybik A, Słowik A, et al. (2021) Neurogranin and neuronal pentraxin receptor as synaptic dysfunction biomarkers in Alzheimer's disease. J Clin Med 10: 4575. https://doi.org/10.3390/jcm10194575 |
[27] | MacMahon Copas AN, McComish SF, Fletcher JM, et al. (2021) The pathogenesis of Parkinson's disease: A complex interplay between astrocytes, microglia, and T lymphocytes?. Front Neurol 12. https://doi.org/10.3389/fneur.2021.666737 |
[28] | Lotharius J, Brundin P (2002) Pathogenesis of parkinson's disease: dopamine, vesicles and α-synuclein. Nat Rev Neurosci 3: 932-942. https://doi.org/10.1038/nrn983 |
[29] | Adam H, Gopinath SCB, Md Arshad MK, et al. (2023) An update on pathogenesis and clinical scenario for Parkinson's disease: diagnosis and treatment. 3 Biotech 13. https://doi.org/10.1007/s13205-023-03553-8 |
[30] | Warth Perez Arias CC, Silbern I, Caldi Gomes L, et al. (2023) Proteomic analysis of the human hippocampus identifies neuronal pentraxin 1 (NPTX1) as synapto-axonal target in late-stage Parkinson's disease. J Neurochem 166: 862-874. https://doi.org/10.1111/jnc.15924 |
[31] | Roh SE, Xiao M, Delgado A, et al. (2023) Sleep and circadian rhythm disruption by NPTX2 loss of function. bioRxiv . https://doi.org/10.1101/2023.09.26.559408 |
[32] | van der Ende EL, Xiao M, Xu D, et al. (2020) Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia. J Neurol Neurosurg Psychiatry 91: 612-621. https://doi.org/10.1136/jnnp-2019-322493 |
[33] | Lakhan SE, Vieira KF (2009) Schizophrenia pathophysiology: are we any closer to a complete model?. Ann Gen Psychiatry 8: 12. https://doi.org/10.1186/1744-859X-8-12 |
[34] | Howes OD, Murray RM (2014) Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet 383: 1677-1687. https://doi.org/10.1016/S0140-6736(13)62036-X |
[35] | Kantrowitz JT, Javitt DC (2010) N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: The final common pathway on the road to schizophrenia?. Brain Res Bull 83: 108-121. https://doi.org/10.1016/j.brainresbull.2010.04.006 |
[36] | Neniskyte U, Gross CT (2017) Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci 18: 658-670. https://doi.org/10.1038/nrn.2017.110 |
[37] | Volk L, Chiu SL, Sharma K, et al. (2015) Glutamate synapses in human cognitive disorders. Annu Rev Neurosci 38: 127-149. https://doi.org/10.1146/annurev-neuro-071714-033821 |
[38] | Vallée A (2022) Neuroinflammation in schizophrenia: The key role of the WNT/β-catenin pathway. Int J Mol Sci 23: 2810. https://doi.org/10.3390/ijms23052810 |
[39] | Du J, Quiroz J, Yuan P, et al. (2004) Bipolar disorder: involvement of signaling cascades and AMPA receptor trafficking at synapses. Neuron Glia Biol 1: 231-243. https://doi.org/10.1017/S1740925X05000098 |
[40] | de Lara CL, Jaitovich-Groisman I, Cruceanu C, et al. (2010) Implication of synapse-related genes in bipolar disorder by linkage and gene expression analyses. Int J Neuropsychopharmacol 13: 1397-1410. https://doi.org/10.1017/S1461145710000714 |
[41] | Grande I, Berk M, Birmaher B, et al. (2016) Bipolar disorder. Lancet 387: 1561-1572. https://doi.org/10.1016/S0140-6736(15)00241-X |
[42] | Comer AL, Jinadasa T, Sriram B, et al. (2020) Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction. PLoS Biol 18: e3000604. https://doi.org/10.1371/journal.pbio.3000604 |
[43] | Yilmaz M, Yalcin E, Presumey J, et al. (2021) Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice. Nat Neurosci 24: 214-224. https://doi.org/10.1038/s41593-020-00763-8 |
[44] | Manchia M, Piras IS, Huentelman MJ, et al. (2017) Pattern of gene expression in different stages of schizophrenia: Down-regulation of NPTX2 gene revealed by a meta-analysis of microarray datasets. Eur Neuropsychopharmacol 27: 1054-1063. https://doi.org/10.1016/j.euroneuro.2017.07.002 |
[45] | Piras IS, Manchia M, Huentelman MJ, et al. (2019) Peripheral biomarkers in schizophrenia: A meta-analysis of microarray gene expression datasets. Int J Neuropsychopharmacol 22: 186-193. https://doi.org/10.1093/ijnp/pyy103 |
[46] | Göverti D, Büyüklüoğlu N, Kaya H, et al. (2022) Neuronal pentraxin-2 (NPTX2) serum levels during an acute psychotic episode in patients with schizophrenia. Psychopharmacology 239: 2585-2591. https://doi.org/10.1007/s00213-022-06147-z |
[47] | Bian Y, Kawabata R, Enwright JF, et al. (2024) Expression of activity-regulated transcripts in pyramidal neurons across the cortical visuospatial working memory network in unaffected comparison individuals and individuals with schizophrenia. Psychiatry Res 339: 116084. https://doi.org/10.1016/j.psychres.2024.116084 |
[48] | Knorr U, Simonsen AH, Nilsson J, et al. (2024) Cerebrospinal fluid synaptic biomarker changes in bipolar disorder – A longitudinal case-control study. J Affect Disord 358: 250-259. https://doi.org/10.1016/j.jad.2024.05.034 |
[49] | Aryal S, Bonanno K, Song B, et al. (2023) Deep proteomics identifies shared molecular pathway alterations in synapses of patients with schizophrenia and bipolar disorder and mouse model. Cell Rep 42: 112497. https://doi.org/10.1016/j.celrep.2023.112497 |
[50] | Strauss J, McGregor S, Freeman N, et al. (2012) Association study of early-immediate genes in childhood-onset mood disorders and suicide attempt. Psychiatry Res 197: 49-54. https://doi.org/10.1016/j.psychres.2011.11.022 |
[51] | Colloca L, Ludman T, Bouhassira D, et al. (2017) Neuropathic pain. Nat Rev Dis Primers 3: 1-19. https://doi.org/10.1038/nrdp.2017.2 |
[52] | Cavalli E, Mammana S, Nicoletti F, et al. (2019) The neuropathic pain: An overview of the current treatment and future therapeutic approaches. Int J Immunopathol Pharmacol 33: 205873841983838. https://doi.org/10.1177/2058738419838383 |
[53] | TerminologyInternational Association for the Study of Pain (IASP) (2021). Published March 30, 2021. Accessed August 5, 2024. https://www.iasp-pain.org/resources/terminology/ |
[54] | Miskimon M, Han S, Lee JJ, et al. (2014) Selective expression of Narp in primary nociceptive neurons: Role in microglia/macrophage activation following nerve injury. J Neuroimmunol 274: 86-95. https://doi.org/10.1016/j.jneuroim.2014.06.016 |
[55] | Shneker BF, Fountain NB (2003) Epilepsy. Dis Mon 49: 426-478. https://doi.org/10.1016/S0011-5029(03)00065-8 |
[56] | Novak A, Vizjak K, Rakusa M (2022) Cognitive impairment in people with epilepsy. J Clin Med 11: 267. https://doi.org/10.3390/jcm11010267 |
[57] | Xing M, Yang X, Jin S, et al. (2024) Inhibition of neuronal pentraxin 2 relieved epileptic seizure via reducing GluA1 phosphorylation. Cell Biochem Funct 42. https://doi.org/10.1002/cbf.4003 |
[58] | Hossain MA (2005) Molecular mediators of hypoxic–ischemic injury and implications for epilepsy in the developing brain. Epilepsy Behav 7: 204-213. https://doi.org/10.1016/j.yebeh.2005.05.015 |
[59] | Traxinger K, Kelly C, Johnson BA, et al. (2013) Prognosis and epidemiology of amyotrophic lateral sclerosis: Analysis of a clinic population, 1997-2011. Neurol Clin Pract 3: 313-320. https://doi.org/10.1212/CPJ.0b013e3182a1b8ab |
[60] | Devine MS, Kiernan MC, Heggie S, et al. (2014) Study of motor asymmetry in ALS indicates an effect of limb dominance on onset and spread of weakness, and an important role for upper motor neurons. Amyotroph Lateral Scler Frontotemporal Degener 15: 481-487. https://doi.org/10.3109/21678421.2014.906617 |
[61] | Sciencedirect.com. Accessed August 5, 2024. https://www.sciencedirect.com/science/article/abs/pii/B9780323957021001202?fr=RR-2&ref=pdf_download&rr=8ae5a4b07fdb31a3 |
[62] | Lillo P, Hodges JR (2009) Frontotemporal dementia and motor neurone disease: Overlapping clinic-pathological disorders. J Clin Neurosci 16: 1131-1135. https://doi.org/10.1016/j.jocn.2009.03.005 |
[63] | Jo M, Lee S, Jeon YM, et al. (2020) The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies. Exp Mol Med 52: 1652-1662. https://doi.org/10.1038/s12276-020-00513-7 |