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image of Roles of C/EBPβ/AEP in Neurodegenerative Diseases

Abstract

In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α-synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.

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/content/journals/ctmc/10.2174/0115680266357822250119172351
2025-01-27
2025-06-30
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References

  1. Collinge J. Mammalian prions and their wider relevance in neurodegenerative diseases. Nature 2016 539 7628 217 226 10.1038/nature20415 27830781
    [Google Scholar]
  2. Fu H. Hardy J. Duff K.E. Selective vulnerability in neurodegenerative diseases. Nat. Neurosci. 2018 21 10 1350 1358 10.1038/s41593‑018‑0221‑2 30250262
    [Google Scholar]
  3. Chung C.G. Lee H. Lee S.B. Mechanisms of protein toxicity in neurodegenerative diseases. Cell. Mol. Life Sci. 2018 75 17 3159 3180 10.1007/s00018‑018‑2854‑4 29947927
    [Google Scholar]
  4. Guzman-Martinez L. Maccioni R.B. Andrade V. Navarrete L.P. Pastor M.G. Ramos-Escobar N. Neuroinflammation as a common feature of neurodegenerative disorders. Front. Pharmacol. 2019 10 1008 10.3389/fphar.2019.01008 31572186
    [Google Scholar]
  5. Chen X.Q. Mobley W.C. Exploring the pathogenesis of Alzheimer disease in basal forebrain cholinergic neurons: Converging insights from alternative hypotheses. Front. Neurosci. 2019 13 446 10.3389/fnins.2019.00446 31133787
    [Google Scholar]
  6. Dugger B.N. Dickson D.W. Pathology of neurodegenerative diseases. Cold Spring Harb. Perspect. Biol. 2017 9 7 a028035 10.1101/cshperspect.a028035 28062563
    [Google Scholar]
  7. Gan L. Cookson M.R. Petrucelli L. La Spada A.R. Converging pathways in neurodegeneration, from genetics to mechanisms. Nat. Neurosci. 2018 21 10 1300 1309 10.1038/s41593‑018‑0237‑7 30258237
    [Google Scholar]
  8. Wilson D.M. III Cookson M.R. Van Den Bosch L. Zetterberg H. Holtzman D.M. Dewachter I. Hallmarks of neurodegenerative diseases. Cell 2023 186 4 693 714 10.1016/j.cell.2022.12.032 36803602
    [Google Scholar]
  9. Chen J.M. Dando P.M. Rawlings N.D. Brown M.A. Young N.E. Stevens R.A. Hewitt E. Watts C. Barrett A.J. Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. J. Biol. Chem. 1997 272 12 8090 8098 10.1074/jbc.272.12.8090 9065484
    [Google Scholar]
  10. Wang Z.H. Liu P. Liu X. Yu S.P. Wang J.Z. Ye K. Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies. J. Exp. Med. 2018 215 12 3038 3056 10.1084/jem.20180539 30373880
    [Google Scholar]
  11. Zhang Z. Song M. Liu X. Su Kang S. Duong D.M. Seyfried N.T. Cao X. Cheng L. Sun Y.E. Ping Yu S. Jia J. Levey A.I. Ye K. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease. Nat. Commun. 2015 6 1 8762 10.1038/ncomms9762 26549211
    [Google Scholar]
  12. Kang S.S. Ahn E.H. Zhang Z. Liu X. Manfredsson F.P. Sandoval I.M. Dhakal S. Iuvone P.M. Cao X. Ye K. α‐Synuclein stimulation of monoamine oxidase‐B and legumain protease mediates the pathology of Parkinson’s disease. EMBO J. 2018 37 12 e98878 10.15252/embj.201798878 29769405
    [Google Scholar]
  13. Herskowitz J.H. Gozal Y.M. Duong D.M. Dammer E.B. Gearing M. Ye K. Lah J.J. Peng J. Levey A.I. Seyfried N.T. Asparaginyl endopeptidase cleaves TDP‐43 in brain. Proteomics 2012 12 15-16 2455 2463 10.1002/pmic.201200006 22718532
    [Google Scholar]
  14. Hara-Nishimura I. Inoue K. Nishimura M. A unique vacuolar processing enzyme responsible for conversion of several proprotein precursors into the mature forms. FEBS Lett. 1991 294 1-2 89 93 10.1016/0014‑5793(91)81349‑D 1743299
    [Google Scholar]
  15. Yamada K. Basak A.K. Goto-Yamada S. Tarnawska-Glatt K. Hara-Nishimura I. Vacuolar processing enzymes in the plant life cycle. New Phytol. 2020 226 1 21 31 10.1111/nph.16306 31679161
    [Google Scholar]
  16. Dall E. Brandstetter H. Mechanistic and structural studies on legumain explain its zymogenicity, distinct activation pathways, and regulation. Proc. Natl. Acad. Sci. USA 2013 110 27 10940 10945 10.1073/pnas.1300686110 23776206
    [Google Scholar]
  17. Zhao L. Hua T. Crowley C. Ru H. Ni X. Shaw N. Jiao L. Ding W. Qu L. Hung L.W. Huang W. Liu L. Ye K. Ouyang S. Cheng G. Liu Z.J. Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage. Cell Res. 2014 24 3 344 358 10.1038/cr.2014.4 24407422
    [Google Scholar]
  18. Rawlings N.D. Barrett A.J. Families of cysteine peptidases. Methods Enzymol. 1994 244 461 486 10.1016/0076‑6879(94)44034‑4 7845226
    [Google Scholar]
  19. Dall E. Stanojlovic V. Demir F. Briza P. Dahms S.O. Huesgen P.F. Cabrele C. Brandstetter H. The peptide ligase activity of human legumain depends on fold stabilization and balanced substrate affinities. ACS Catal. 2021 11 19 11885 11896 10.1021/acscatal.1c02057 34621593
    [Google Scholar]
  20. Ni J. Abrahamson M. Zhang M. Fernandez M.A. Grubb A. Su J. Yu G.L. Li Y. Parmelee D. Xing L. Coleman T.A. Gentz S. Thotakura R. Nguyen N. Hesselberg M. Gentz R. Cystatin E is a novel human cysteine proteinase inhibitor with structural resemblance to family 2 cystatins. J. Biol. Chem. 1997 272 16 10853 10858 10.1074/jbc.272.16.10853 9099741
    [Google Scholar]
  21. Alvarez-Fernandez M. Barrett A.J. Gerhartz B. Dando P.M. Ni J. Abrahamson M. Inhibition of mammalian legumain by some cystatins is due to a novel second reactive site. J. Biol. Chem. 1999 274 27 19195 19203 10.1074/jbc.274.27.19195 10383426
    [Google Scholar]
  22. Cheng T. Hitomi K. van Vlijmen-Willems I.M.J.J. de Jongh G.J. Yamamoto K. Nishi K. Watts C. Reinheckel T. Schalkwijk J. Zeeuwen P.L.J.M. Cystatin M/E is a high affinity inhibitor of cathepsin V and cathepsin L by a reactive site that is distinct from the legumain-binding site. A novel clue for the role of cystatin M/E in epidermal cornification. J. Biol. Chem. 2006 281 23 15893 15899 10.1074/jbc.M600694200 16565075
    [Google Scholar]
  23. Smith R. Johansen H.T. Nilsen H. Haugen M.H. Pettersen S.J. Mælandsmo G.M. Abrahamson M. Solberg R. Intra- and extracellular regulation of activity and processing of legumain by cystatin E/M. Biochimie 2012 94 12 2590 2599 10.1016/j.biochi.2012.07.026 22902879
    [Google Scholar]
  24. Dall E. Fegg J.C. Briza P. Brandstetter H. Structure and mechanism of an aspartimide-dependent peptide ligase in human legumain. Angew. Chem. Int. Ed. 2015 54 10 2917 2921 10.1002/anie.201409135 25630877
    [Google Scholar]
  25. Miller G. Matthews S.P. Reinheckel T. Fleming S. Watts C. Asparagine endopeptidase is required for normal kidney physiology and homeostasis. FASEB J. 2011 25 5 1606 1617 10.1096/fj.10‑172312 21292981
    [Google Scholar]
  26. Sepulveda F.E. Maschalidi S. Colisson R. Heslop L. Ghirelli C. Sakka E. Lennon-Duménil A.M. Amigorena S. Cabanie L. Manoury B. Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. Immunity 2009 31 5 737 748 10.1016/j.immuni.2009.09.013 19879164
    [Google Scholar]
  27. Chan C.B. Abe M. Hashimoto N. Hao C. Williams I.R. Liu X. Nakao S. Yamamoto A. Zheng C. Henter J.I. Meeths M. Nordenskjold M. Li S.Y. Hara-Nishimura I. Asano M. Ye K. Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome. Proc. Natl. Acad. Sci. USA 2009 106 2 468 473 10.1073/pnas.0809824105 19106291
    [Google Scholar]
  28. Manoury B. Mazzeo D. Li D.N. Billson J. Loak K. Benaroch P. Watts C. Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone. Immunity 2003 18 4 489 498 10.1016/S1074‑7613(03)00085‑2 12705852
    [Google Scholar]
  29. Chen J.M. Fortunato M. Stevens R.A.E. Barrett A.J. Activation of progelatinase A by mammalian legumain, a recently discovered cysteine proteinase. bchm 2001 382 5 777 784 10.1515/bchm.2001.382.5.777 11517930
    [Google Scholar]
  30. Liu Z. Jang S.W. Liu X. Cheng D. Peng J. Yepes M. Li X. Matthews S. Watts C. Asano M. Hara-Nishimura I. Luo H.R. Ye K. Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase. Mol. Cell 2008 29 6 665 678 10.1016/j.molcel.2008.02.017 18374643
    [Google Scholar]
  31. Wang Z.H. Gong K. Liu X. Zhang Z. Sun X. Wei Z.Z. Yu S.P. Manfredsson F.P. Sandoval I.M. Johnson P.F. Jia J. Wang J.Z. Ye K. C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease. Nat. Commun. 2018 9 1 1784 10.1038/s41467‑018‑04120‑z 29725016
    [Google Scholar]
  32. Ramji D.P. Foka P. CCAAT/enhancer-binding proteins: Structure, function and regulation. Biochem. J. 2002 365 3 561 575 10.1042/bj20020508 12006103
    [Google Scholar]
  33. Suh Y.H. Kim W.H. Moon C. Hong Y.H. Eun S.Y. Lim J.H. Choi J.S. Song J. Jung M.H. Ectopic expression of Neuronatin potentiates adipogenesis through enhanced phosphorylation of cAMP-response element-binding protein in 3T3-L1 cells. Biochem. Biophys. Res. Commun. 2005 337 2 481 489 10.1016/j.bbrc.2005.09.078 16223607
    [Google Scholar]
  34. Basu S.K. Malik R. Huggins C.J. Lee S. Sebastian T. Sakchaisri K. Quiñones O.A. Alvord W.G. Johnson P.F. 3′UTR elements inhibit Ras-induced C/EBPβ post-translational activation and senescence in tumour cells. EMBO J. 2011 30 18 3714 3728 10.1038/emboj.2011.250 21804532
    [Google Scholar]
  35. Cloutier A. Guindi C. Larivée P. Dubois C.M. Amrani A. McDonald P.P. Inflammatory cytokine production by human neutrophils involves C/EBP transcription factors. J. Immunol. 2009 182 1 563 571 10.4049/jimmunol.182.1.563 19109189
    [Google Scholar]
  36. Straccia M. Gresa-Arribas N. Dentesano G. Ejarque-Ortiz A. Tusell J.M. Serratosa J. Solà C. Saura J. Pro-inflammatory gene expression and neurotoxic effects of activated microglia are attenuated by absence of CCAAT/enhancer binding protein β. J. Neuroinflammation 2011 8 1 156 10.1186/1742‑2094‑8‑156 22074460
    [Google Scholar]
  37. Trautwein C. Caelles C. van der Geer P. Hunter T. Karin M. Chojkier M. Transactivation by NF-IL6/LAP is enhanced by phosphorylation of its activation domain. Nature 1993 364 6437 544 547 10.1038/364544a0 8336793
    [Google Scholar]
  38. Hungness E.S. Luo G. Pritts T.A. Sun X. Robb B.W. Hershko D. Hasselgren P.O. Transcription factors C/EBP‐β and ‐δ regulate IL‐6 production in IL‐1β‐stimulated human enterocytes. J. Cell. Physiol. 2002 192 1 64 70 10.1002/jcp.10116 12115737
    [Google Scholar]
  39. van der Krieken S.E. Popeijus H.E. Mensink R.P. Plat J. CCAAT/enhancer binding protein β in relation to ER stress, inflammation, and metabolic disturbances. BioMed Res. Int. 2015 2015 1 13 10.1155/2015/324815 25699273
    [Google Scholar]
  40. Seufert J. Weir G.C. Habener J.F. Differential expression of the insulin gene transcriptional repressor CCAAT/enhancer-binding protein beta and transactivator islet duodenum homeobox-1 in rat pancreatic beta cells during the development of diabetes mellitus. J. Clin. Invest. 1998 101 11 2528 2539 10.1172/JCI2401 9616224
    [Google Scholar]
  41. Lu M. Seufert J. Habener J.F. Pancreatic beta-cell-specific repression of insulin gene transcription by CCAAT/enhancer-binding protein beta. Inhibitory interactions with basic helix-loop-helix transcription factor E47. J. Biol. Chem. 1997 272 45 28349 28359 10.1074/jbc.272.45.28349 9353292
    [Google Scholar]
  42. Chen B. Wang M. Huang R. Liao K. Wang T. Yang R. Zhang W. Shi Z. Ren L. Lv Q. Ma C. Lin Y. Qiu Y. Circular RNA circLGMN facilitates glioblastoma progression by targeting miR-127-3p/LGMN axis. Cancer Lett. 2021 522 225 237 10.1016/j.canlet.2021.09.030 34582975
    [Google Scholar]
  43. Iqbal S. Malik M.Z. Pal D. Network-based identification of miRNAs and transcription factors and in silico drug screening targeting δ-secretase involved in Alzheimer’s disease. Heliyon 2021 7 12 e08502 10.1016/j.heliyon.2021.e08502 34917801
    [Google Scholar]
  44. Liu Y. Wang Y. Shen X. Chen C. Ni H. Sheng N. Hua M. Wu Y. Down-regulation of lncRNA PCGEM1 inhibits cervical carcinoma by modulating the miR-642a-5p/LGMN axis. Exp. Mol. Pathol. 2020 117 104561 10.1016/j.yexmp.2020.104561 33121976
    [Google Scholar]
  45. Zhang Y. Wu Y. Jiang J. Liu X. Ji F. Fang X. MiRNA-3978 regulates peritoneal gastric cancer metastasis by targeting legumain. Oncotarget 2016 7 50 83223 83230 10.18632/oncotarget.12917 27793040
    [Google Scholar]
  46. Herrup K. Reimagining Alzheimer’s disease--an age-based hypothesis. J. Neurosci. 2010 30 50 16755 16762 10.1523/JNEUROSCI.4521‑10.2010 21159946
    [Google Scholar]
  47. Müller U.C. Deller T. Korte M. Not just amyloid: Physiological functions of the amyloid precursor protein family. Nat. Rev. Neurosci. 2017 18 5 281 298 10.1038/nrn.2017.29 28360418
    [Google Scholar]
  48. Zhang Z. Obianyo O. Dall E. Du Y. Fu H. Liu X. Kang S.S. Song M. Yu S.P. Cabrele C. Schubert M. Li X. Wang J.Z. Brandstetter H. Ye K. Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease. Nat. Commun. 2017 8 1 14740 10.1038/ncomms14740 28345579
    [Google Scholar]
  49. Wang S.S. Liu Z.K. Liu J.J. Cheng Q. Wang Y.X. Liu Y. Ni W.W. Chen H.Z. Song M. Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer’s disease. J. Nanobiotechnology 2021 19 1 249 10.1186/s12951‑021‑00988‑0 34412639
    [Google Scholar]
  50. Selkoe D.J. The molecular pathology of Alzheimer’s disease. Neuron 1991 6 4 487 498 10.1016/0896‑6273(91)90052‑2 1673054
    [Google Scholar]
  51. Baumann K. Mandelkow E.M. Biernat J. Piwnica-Worms H. Mandelkow E. Abnormal Alzheimer‐like phosphorylation of tau‐protein by cyclin‐dependent kinases cdk2 and cdk5. FEBS Lett. 1993 336 3 417 424 10.1016/0014‑5793(93)80849‑P 8282104
    [Google Scholar]
  52. Kosik K.S. Joachim C.L. Selkoe D.J. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl. Acad. Sci. USA 1986 83 11 4044 4048 10.1073/pnas.83.11.4044 2424016
    [Google Scholar]
  53. Huang F. Wang M. Liu R. Wang J.Z. Schadt E. Haroutunian V. Katsel P. Zhang B. Wang X. CDT2‐controlled cell cycle reentry regulates the pathogenesis of Alzheimer’s disease. Alzheimers Dement. 2019 15 2 217 231 10.1016/j.jalz.2018.08.013 30321504
    [Google Scholar]
  54. Li M. Makkinje A. Damuni Z. The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. J. Biol. Chem. 1996 271 19 11059 11062 10.1074/jbc.271.19.11059 8626647
    [Google Scholar]
  55. Seo S. McNamara P. Heo S. Turner A. Lane W.S. Chakravarti D. Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the set oncoprotein. Cell 2001 104 1 119 130 10.1016/S0092‑8674(01)00196‑9 11163245
    [Google Scholar]
  56. Zhang Z. Song M. Liu X. Kang S.S. Kwon I.S. Duong D.M. Seyfried N.T. Hu W.T. Liu Z. Wang J.Z. Cheng L. Sun Y.E. Yu S.P. Levey A.I. Ye K. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat. Med. 2014 20 11 1254 1262 10.1038/nm.3700 25326800
    [Google Scholar]
  57. Hardy J. Selkoe D.J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 2002 297 5580 353 356 10.1126/science.1072994 12130773
    [Google Scholar]
  58. Selkoe D.J. Amyloid beta-protein and the genetics of Alzheimer’s disease. J. Biol. Chem. 1996 271 31 18295 18298 10.1074/jbc.271.31.18295 8756120
    [Google Scholar]
  59. Khan S. Barve K.H. Kumar M.S. Recent advancements in pathogenesis, diagnostics and treatment of Alzheimer’s disease. Curr. Neuropharmacol. 2020 18 11 1106 1125 10.2174/1570159X18666200528142429 32484110
    [Google Scholar]
  60. Lendon C.L. Ashall F. Goate A.M. Exploring the etiology of Alzheimer disease using molecular genetics. JAMA 1997 277 10 825 831 10.1001/jama.1997.03540340059034 9052714
    [Google Scholar]
  61. Liu X. Liu Y. Liu J. Zhang H. Shan C. Guo Y. Gong X. Cui M. Li X. Tang M. Correlation between the gut microbiome and neurodegenerative diseases: A review of metagenomics evidence. Neural Regen. Res. 2024 19 4 833 845 10.4103/1673‑5374.382223 37843219
    [Google Scholar]
  62. Cammann D. Lu Y. Cummings M.J. Zhang M.L. Cue J.M. Do J. Ebersole J. Chen X. Oh E.C. Cummings J.L. Chen J. Genetic correlations between Alzheimer’s disease and gut microbiome genera. Sci. Rep. 2023 13 1 5258 10.1038/s41598‑023‑31730‑5 37002253
    [Google Scholar]
  63. Chen C. Ahn E.H. Kang S.S. Liu X. Alam A. Ye K. Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in Alzheimer’s disease mouse model. Sci. Adv. 2020 6 31 eaba0466 10.1126/sciadv.aba0466 32832679
    [Google Scholar]
  64. Talbot K. Wang H.Y. Kazi H. Han L.Y. Bakshi K.P. Stucky A. Fuino R.L. Kawaguchi K.R. Samoyedny A.J. Wilson R.S. Arvanitakis Z. Schneider J.A. Wolf B.A. Bennett D.A. Trojanowski J.Q. Arnold S.E. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest. 2012 122 4 1316 1338 10.1172/JCI59903 22476197
    [Google Scholar]
  65. Duan Y. Zeng L. Zheng C. Song B. Li F. Kong X. Xu K. Inflammatory links between high fat diets and diseases. Front. Immunol. 2018 9 2649 10.3389/fimmu.2018.02649 30483273
    [Google Scholar]
  66. Janson J. Laedtke T. Parisi J.E. O’Brien P. Petersen R.C. Butler P.C. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 2004 53 2 474 481 10.2337/diabetes.53.2.474 14747300
    [Google Scholar]
  67. Yao Q. Long C. Yi P. Zhang G. Wan W. Rao X. Ying J. Liang W. Hua F. C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer’s disease. CNS Neurosci. Ther. 2024 30 4 e14721 10.1111/cns.14721 38644578
    [Google Scholar]
  68. Xia Y. Qadota H. Wang Z.H. Liu P. Liu X. Ye K.X. Matheny C.J. Berglund K. Yu S.P. Drake D. Bennett D.A. Wang X.C. Yankner B.A. Benian G.M. Ye K. Neuronal C/EBPβ/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression. Sci. Adv. 2022 8 13 eabj8658 10.1126/sciadv.abj8658 35353567
    [Google Scholar]
  69. Liao J. Chen G. Liu X. Wei Z.Z. Yu S.P. Chen Q. Ye K. C/EBPβ/AEP signaling couples atherosclerosis to the pathogenesis of Alzheimer’s disease. Mol. Psychiatry 2022 27 7 3034 3046 10.1038/s41380‑022‑01556‑0 35422468
    [Google Scholar]
  70. Bang J. Spina S. Miller B.L. Frontotemporal dementia. Lancet 2015 386 10004 1672 1682 10.1016/S0140‑6736(15)00461‑4 26595641
    [Google Scholar]
  71. Zhang Z. Tian Y. Ye K. δ-secretase in neurodegenerative diseases: Mechanisms, regulators and therapeutic opportunities. Transl. Neurodegener. 2020 9 1 1 10.1186/s40035‑019‑0179‑3 31911834
    [Google Scholar]
  72. Wang Z.H. Xiang J. Liu X. Yu S.P. Manfredsson F.P. Sandoval I.M. Wu S. Wang J.Z. Ye K. Deficiency in BDNF/TrkB neurotrophic activity stimulates δ-Secretase by upregulating C/EBPβ in Alzheimer’s disease. Cell Rep. 2019 28 3 655 669.e5 10.1016/j.celrep.2019.06.054 31315045
    [Google Scholar]
  73. Mackenzie I.R.A. Rademakers R. Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 2010 9 10 995 1007 10.1016/S1474‑4422(10)70195‑2 20864052
    [Google Scholar]
  74. Martinez-Martin P. The importance of non-motor disturbances to quality of life in Parkinson’s disease. J. Neurol. Sci. 2011 310 1-2 12 16 10.1016/j.jns.2011.05.006 21621226
    [Google Scholar]
  75. Braak H Del TK Bratzke H Hamm-Clement J Sandmann-Keil D Rub U Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages). J Neurol. 2002 249 Suppl 3 III/1-5 10.1007/s00415‑002‑1301‑4 12528692
    [Google Scholar]
  76. Zhang Z. Kang S.S. Liu X. Ahn E.H. Zhang Z. He L. Iuvone P.M. Duong D.M. Seyfried N.T. Benskey M.J. Manfredsson F.P. Jin L. Sun Y.E. Wang J.Z. Ye K. Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson’s disease. Nat. Struct. Mol. Biol. 2017 24 8 632 642 10.1038/nsmb.3433 28671665
    [Google Scholar]
  77. Wang H. Chen G. Ahn E.H. Xia Y. Kang S.S. Liu X. Liu C. Han M.H. Chen S. Ye K. C/EBPβ/AEP is age-dependently activated in Parkinson’s disease and mediates α-synuclein in the gut and brain. NPJ Parkinsons Dis. 2023 9 1 1 10.1038/s41531‑022‑00430‑8 36609384
    [Google Scholar]
  78. Sidransky E. Nalls M.A. Aasly J.O. Aharon-Peretz J. Annesi G. Barbosa E.R. Bar-Shira A. Berg D. Bras J. Brice A. Chen C.M. Clark L.N. Condroyer C. De Marco E.V. Dürr A. Eblan M.J. Fahn S. Farrer M.J. Fung H.C. Gan-Or Z. Gasser T. Gershoni-Baruch R. Giladi N. Griffith A. Gurevich T. Januario C. Kropp P. Lang A.E. Lee-Chen G.J. Lesage S. Marder K. Mata I.F. Mirelman A. Mitsui J. Mizuta I. Nicoletti G. Oliveira C. Ottman R. Orr-Urtreger A. Pereira L.V. Quattrone A. Rogaeva E. Rolfs A. Rosenbaum H. Rozenberg R. Samii A. Samaddar T. Schulte C. Sharma M. Singleton A. Spitz M. Tan E.K. Tayebi N. Toda T. Troiano A.R. Tsuji S. Wittstock M. Wolfsberg T.G. Wu Y.R. Zabetian C.P. Zhao Y. Ziegler S.G. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N. Engl. J. Med. 2009 361 17 1651 1661 10.1056/NEJMoa0901281 19846850
    [Google Scholar]
  79. Polymeropoulos M.H. Lavedan C. Leroy E. Ide S.E. Dehejia A. Dutra A. Pike B. Root H. Rubenstein J. Boyer R. Stenroos E.S. Chandrasekharappa S. Athanassiadou A. Papapetropoulos T. Johnson W.G. Lazzarini A.M. Duvoisin R.C. Di Iorio G. Golbe L.I. Nussbaum R.L. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997 276 5321 2045 2047 10.1126/science.276.5321.2045 9197268
    [Google Scholar]
  80. Lesage S. Drouet V. Majounie E. Deramecourt V. Jacoupy M. Nicolas A. Cormier-Dequaire F. Hassoun S.M. Pujol C. Ciura S. Erpapazoglou Z. Usenko T. Maurage C.A. Sahbatou M. Liebau S. Ding J. Bilgic B. Emre M. Erginel-Unaltuna N. Guven G. Tison F. Tranchant C. Vidailhet M. Corvol J.C. Krack P. Leutenegger A.L. Nalls M.A. Hernandez D.G. Heutink P. Gibbs J.R. Hardy J. Wood N.W. Gasser T. Durr A. Deleuze J.F. Tazir M. Destée A. Lohmann E. Kabashi E. Singleton A. Corti O. Brice A. Lesage S. Tison F. Vidailhet M. Corvol J-C. Agid Y. Anheim M. Bonnet A-M. Borg M. Broussolle E. Damier P. Destée A. Dürr A. Durif F. Krack P. Klebe S. Lohmann E. Martinez M. Pollak P. Rascol O. Tranchant C. Vérin M. Viallet F. Brice A. Lesage S. Majounie E. Tison F. Vidailhet M. Corvol J.C. Nalls M.A. Hernandez D.G. Gibbs J.R. Dürr A. Arepalli S. Barker R.A. Ben-Shlomo Y. Berg D. Bettella F. Bhatia K. de Bie R.M.A. Biffi A. Bloem B.R. Bochdanovits Z. Bonin M. Lesage S. Tison F. Vidailhet M. Corvol J-C. Agid Y. Anheim M. Bonnet A-M. Borg M. Broussolle E. Damier P. Destée A. Dürr A. Durif F. Krack P. Klebe S. Lohmann E. Martinez M. Pollak P. Rascol O. Tranchant C. Vérin M. Bras J.M. Brockmann K. Brooks J. Burn D.J. Charlesworth G. Chen H. Chinnery P.F. Chong S. Clarke C.E. Cookson M.R. Counsell C. Damier P. Dartigues J-F. Deloukas P. Deuschl G. Dexter D.T. van Dijk K.D. Dillman A. Dong J. Durif F. Edkins S. Escott-Price V. Evans J.R. Foltynie T. Gao J. Gardner M. Goate A. Gray E. Guerreiro R. Harris C. van Hilten J.J. Hofman A. Hollenbeck A. Holmans P. Holton J. Hu M. Huang X. Huber H. Hudson G. Hunt S.E. Huttenlocher J. Illig T. Jónsson P.V. Kilarski L.L. Jansen I.E. Lambert J-C. Langford C. Lees A. Lichtner P. Limousin P. Lopez G. Lorenz D. Lubbe S. Lungu C. Martinez M. Mätzler W. McNeill A. Moorby C. Moore M. Morrison K.E. Mudanohwo E. O’Sullivan S.S. Owen M.J. Pearson J. Perlmutter J.S. Pétursson H. Plagnol V. Pollak P. Post B. Potter S. Ravina B. Revesz T. Riess O. Rivadeneira F. Rizzu P. Ryten M. Saad M. Simón-Sánchez J. Sawcer S. Schapira A. Scheffer H. Schulte C. Sharma M. Shaw K. Sheerin U-M. Shoulson I. Shulman J. Sidransky E. Spencer C.C.A. Stefánsson H. Stefánsson K. Stockton J.D. Strange A. Talbot K. Tanner C.M. Tashakkori-Ghanbaria A. Trabzuni D. Traynor B.J. Uitterlinden A.G. Velseboer D. Walker R. van de Warrenburg B. Wickremaratchi M. Williams-Gray C.H. Winder-Rhodes S. Wurster I. Williams N. Morris H.R. Heutink P. Hardy J. Wood N.W. Gasser T. Singleton A.B. Brice A. French Parkinson’s Disease Genetics Study (PDG) International Parkinson’s Disease Genomics Consortium (IPDGC) Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/parkin-dependent mitophagy. Am. J. Hum. Genet. 2016 98 3 500 513 10.1016/j.ajhg.2016.01.014 26942284
    [Google Scholar]
  81. Zou L. Zhang X. Xiong M. Meng L. Tian Y. Pan L. Yuan X. Chen G. Wang Z. Bu L. Yao Z. Zhang Z. Ye K. Zhang Z. Asparagine endopeptidase cleaves synaptojanin 1 and triggers synaptic dysfunction in Parkinson’s disease. Neurobiol. Dis. 2021 154 105326 10.1016/j.nbd.2021.105326 33677035
    [Google Scholar]
  82. Fang X. Liu S. Muhammad B. Zheng M. Ge X. Xu Y. Kan S. Zhang Y. Yu Y. Zheng K. Geng D. Liu C.F. Gut microbiota dysbiosis contributes to α-synuclein-related pathology associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson’s disease. Neural Regen. Res. 2024 19 9 2081 2088 10.4103/1673‑5374.391191 38227539
    [Google Scholar]
  83. Ahn E.H. Lei K. Kang S.S. Wang Z.H. Liu X. Hong W. Wang Y.T. Edgington-Mitchell L.E. Jin L. Ye K. Mitochondrial dysfunction triggers the pathogenesis of Parkinson’s disease in neuronal C/EBPβ transgenic mice. Mol. Psychiatry 2021 26 12 7838 7850 10.1038/s41380‑021‑01284‑x 34489530
    [Google Scholar]
  84. Lei K. Shen Y. He Y. Zhang L. Zhang J. Tong W. Xu Y. Jin L. Baicalin represses C/EBP β via its antioxidative effect in Parkinson’s disease. Oxid. Med. Cell. Longev. 2020 2020 1 14 10.1155/2020/8951907 32566108
    [Google Scholar]
  85. Wu Z. Xia Y. Wang Z. Su Kang S. Lei K. Liu X. Jin L. Wang X. Cheng L. Ye K. C/EBPβ/δ-secretase signaling mediates Parkinson’s disease pathogenesis via regulating transcription and proteolytic cleavage of α-synuclein and MAOB. Mol. Psychiatry 2021 26 2 568 585 10.1038/s41380‑020‑0687‑7 32086435
    [Google Scholar]
  86. Morales-Garcia J.A. Gine E. Hernandez-Encinas E. Aguilar-Morante D. Sierra-Magro A. Sanz-SanCristobal M. Alonso-Gil S. Sanchez-Lanzas R. Castaño J.G. Santos A. Perez-Castillo A. CCAAT/Enhancer binding protein β silencing mitigates glial activation and neurodegeneration in a rat model of Parkinson’s disease. Sci. Rep. 2017 7 1 13526 10.1038/s41598‑017‑13269‑4 29051532
    [Google Scholar]
  87. Gao J. Zhang W. Chai X. Tan X. Yang Z. Asparagine endopeptidase deletion ameliorates cognitive impairments by inhibiting proinflammatory microglial activation in MPTP mouse model of Parkinson disease. Brain Res. Bull. 2022 178 120 130 10.1016/j.brainresbull.2021.11.011 34838642
    [Google Scholar]
  88. Valente T. Mancera P. Tusell J.M. Serratosa J. Saura J. C/EBPβ expression in activated microglia in amyotrophic lateral sclerosis. Neurobiol. Aging 2012 33 9 2186 2199 10.1016/j.neurobiolaging.2011.09.019 22015310
    [Google Scholar]
  89. Aghanoori M.R. Agarwal P. Gauvin E. Nagalingam R.S. Bonomo R. Yathindranath V. Smith D.R. Hai Y. Lee S. Jolivalt C.G. Calcutt N.A. Jones M.J. Czubryt M.P. Miller D.W. Dolinsky V.W. Mansuy-Aubert V. Fernyhough P. CEBPβ regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth. Cell. Mol. Life Sci. 2022 79 4 193 10.1007/s00018‑022‑04201‑9 35298717
    [Google Scholar]
  90. Park S.E. Park C.Y. Sweeney G. Biomarkers of insulin sensitivity and insulin resistance: Past, present and future. Crit. Rev. Clin. Lab. Sci. 2015 52 4 180 190 10.3109/10408363.2015.1023429 26042993
    [Google Scholar]
  91. Rauskolb S. Dombert B. Sendtner M. Insulin-like growth factor 1 in diabetic neuropathy and amyotrophic lateral sclerosis. Neurobiol. Dis. 2017 97 Pt B 103 113 10.1016/j.nbd.2016.04.007 27142684
    [Google Scholar]
  92. Lewis M.E. Neff N.T. Contreras P.C. Stong D.B. Oppenheim R.W. Grebow P.E. Vaught J.L. Insulin-like growth factor-I: potential for treatment of motor neuronal disorders. Exp. Neurol. 1993 124 1 73 88 10.1006/exnr.1993.1177 8282084
    [Google Scholar]
  93. Torres-Aleman I. Barrios V. Berciano J. The peripheral insulin-like growth factor system in amyotrophic lateral sclerosis and in multiple sclerosis. Neurology 1998 50 3 772 776 10.1212/WNL.50.3.772 9521273
    [Google Scholar]
  94. Birsa N. Bentham M.P. Fratta P. Cytoplasmic functions of TDP-43 and FUS and their role in ALS. Semin. Cell Dev. Biol. 2020 99 193 201 10.1016/j.semcdb.2019.05.023 31132467
    [Google Scholar]
  95. Zhang N. Gu D. Meng M. Gordon M.L. TDP-43 is elevated in plasma neuronal-derived exosomes of patients with Alzheimer’s disease. Front. Aging Neurosci. 2020 12 166 10.3389/fnagi.2020.00166 32581773
    [Google Scholar]
  96. Sleigh J.N. Tosolini A.P. Gordon D. Devoy A. Fratta P. Fisher E.M.C. Talbot K. Schiavo G. Mice carrying ALS mutant TDP-43, but not mutant FUS, display in vivo defects in axonal transport of signaling endosomes. Cell Rep. 2020 30 11 3655 3662.e2 10.1016/j.celrep.2020.02.078 32187538
    [Google Scholar]
  97. Kim T. Song B. Lee I.S. Drosophila glia: Models for human neurodevelopmental and neurodegenerative disorders. Int. J. Mol. Sci. 2020 21 14 4859 10.3390/ijms21144859 32660023
    [Google Scholar]
  98. Clark J.A. Yeaman E.J. Blizzard C.A. Chuckowree J.A. Dickson T.C. A case for microtubule vulnerability in amyotrophic lateral sclerosis: Altered dynamics during disease. Front. Cell. Neurosci. 2016 10 204 10.3389/fncel.2016.00204 27679561
    [Google Scholar]
  99. Terry D.M. Devine S.E. Aberrantly high levels of somatic LINE-1 expression and retrotransposition in human neurological disorders. Front. Genet. 2020 10 1244 10.3389/fgene.2019.01244 31969897
    [Google Scholar]
  100. Ayala Y.M. Zago P. D’Ambrogio A. Xu Y.F. Petrucelli L. Buratti E. Baralle F.E. Structural determinants of the cellular localization and shuttling of TDP-43. J. Cell Sci. 2008 121 22 3778 3785 10.1242/jcs.038950 18957508
    [Google Scholar]
  101. Kapeli K. Martinez F.J. Yeo G.W. Genetic mutations in RNA-binding proteins and their roles in ALS. Hum. Genet. 2017 136 9 1193 1214 10.1007/s00439‑017‑1830‑7 28762175
    [Google Scholar]
  102. Liao Y.Z. Ma J. Dou J.Z. The role of TDP-43 in neurodegenerative disease. Mol. Neurobiol. 2022 59 7 4223 4241 10.1007/s12035‑022‑02847‑x 35499795
    [Google Scholar]
  103. Polymenidou M. Cleveland D.W. The seeds of neurodegeneration: Prion-like spreading in ALS. Cell 2011 147 3 498 508 10.1016/j.cell.2011.10.011 22036560
    [Google Scholar]
  104. Stürner K.H. Borgmeyer U. Schulze C. Pless O. Martin R. A multiple sclerosis-associated variant of CBLB links genetic risk with type I IFN function. J. Immunol. 2014 193 9 4439 4447 10.4049/jimmunol.1303077 25261476
    [Google Scholar]
  105. Pulido-Salgado M. Vidal-Taboada J.M. Garcia Diaz-Barriga G. Serratosa J. Valente T. Castillo P. Matalonga J. Straccia M. Canals J.M. Valledor A. Solà C. Saura J. Myeloid C/EBPβ deficiency reshapes microglial gene expression and is protective in experimental autoimmune encephalomyelitis. J. Neuroinflammation 2017 14 1 54 10.1186/s12974‑017‑0834‑5 28302135
    [Google Scholar]
  106. Choi E.Y. Lim J-H. Neuwirth A. Economopoulou M. Chatzigeorgiou A. Chung K-J. Bittner S. Lee S-H. Langer H. Samus M. Kim H. Cho G-S. Ziemssen T. Bdeir K. Chavakis E. Koh J-Y. Boon L. Hosur K. Bornstein S.R. Meuth S.G. Hajishengallis G. Chavakis T. Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Mol. Psychiatry 2015 20 7 880 888 10.1038/mp.2014.146 25385367
    [Google Scholar]
  107. Maekawa T. Hosur K. Abe T. Kantarci A. Ziogas A. Wang B. Van Dyke T.E. Chavakis T. Hajishengallis G. Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway. Nat. Commun. 2015 6 1 8272 10.1038/ncomms9272 26374165
    [Google Scholar]
  108. Goris A. Sawcer S. Vandenbroeck K. Carton H. Billiau A. Setakis E. Compston A. Dubois B. New candidate loci for multiple sclerosis susceptibility revealed by a whole genome association screen in a Belgian population. J. Neuroimmunol. 2003 143 1-2 65 69 10.1016/j.jneuroim.2003.08.013 14575916
    [Google Scholar]
  109. Dasgupta S. Jana M. Liu X. Pahan K. Role of very-late antigen-4 (VLA-4) in myelin basic protein-primed T cell contact-induced expression of proinflammatory cytokines in microglial cells. J. Biol. Chem. 2003 278 25 22424 22431 10.1074/jbc.M301789200 12690109
    [Google Scholar]
  110. Jana M. Dasgupta S. Saha R.N. Liu X. Pahan K. Induction of tumor necrosis factor‐α (TNF‐α) by interleukin‐12 p40 monomer and homodimer in microglia and macrophages. J. Neurochem. 2003 86 2 519 528 10.1046/j.1471‑4159.2003.01864.x 12871593
    [Google Scholar]
  111. Dasgupta S. Jana M. Liu X. Pahan K. Myelin basic protein-primed T cells of female but not male mice induce nitric-oxide synthase and proinflammatory cytokines in microglia: Implications for gender bias in multiple sclerosis. J. Biol. Chem. 2005 280 38 32609 32617 10.1074/jbc.M500299200 16046404
    [Google Scholar]
  112. Beck H. Schwarz G. Schröter C.J. Deeg M. Baier D. Stevanovic S. Weber E. Driessen C. Kalbacher H. Cathepsin S and an asparagine-specific endoprotease dominate the proteolytic processing of human myelin basic proteinin vitro. Eur. J. Immunol. 2001 31 12 3726 3736 10.1002/1521‑4141(200112)31:12<3726::AID‑IMMU3726>3.0.CO;2‑O 11745393
    [Google Scholar]
  113. Burster T. Beck A. Tolosa E. Marin-Esteban V. Rötzschke O. Falk K. Lautwein A. Reich M. Brandenburg J. Schwarz G. Wiendl H. Melms A. Lehmann R. Stevanovic S. Kalbacher H. Driessen C. Cathepsin G, and not the asparagine-specific endoprotease, controls the processing of myelin basic protein in lysosomes from human B lymphocytes. J. Immunol. 2004 172 9 5495 5503 10.4049/jimmunol.172.9.5495 15100291
    [Google Scholar]
  114. Schwarz G. Brandenburg J. Reich M. Burster T. Driessen C. Kalbacher H. Characterization of Legumain. Biol. Chem. 2002 383 11 1813 1816 10.1515/BC.2002.203 12530547
    [Google Scholar]
  115. Fernandes H.B. Raymond L.A. NMDA receptors and Huntington's disease. Biology of the NMDA Receptor 2009 17 40
    [Google Scholar]
  116. Obrietan K. Hoyt K.R. CRE-mediated transcription is increased in Huntington’s disease transgenic mice. J. Neurosci. 2004 24 4 791 796 10.1523/JNEUROSCI.3493‑03.2004 14749423
    [Google Scholar]
  117. Lonze B.E. Ginty D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 2002 35 4 605 623 10.1016/S0896‑6273(02)00828‑0 12194863
    [Google Scholar]
  118. Manoury B. Hewitt E.W. Morrice N. Dando P.M. Barrett A.J. Watts C. An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation. Nature 1998 396 6712 695 699 10.1038/25379 9872320
    [Google Scholar]
  119. Niestroj A.J. Feußner K. Heiser U. Dando P.M. Barrett A. Gerhartz B. Demuth H.U. Inhibition of mammalian legumain by Michael acceptors and AzaAsn-halomethylketones. Biol. Chem. 2002 383 7-8 1205 1214 10.1515/BC.2002.133 12437107
    [Google Scholar]
  120. Xu Q.Q. Su Z.R. Yang W. Zhong M. Xian Y.F. Lin Z.X. Patchouli alcohol attenuates the cognitive deficits in a transgenic mouse model of Alzheimer’s disease via modulating neuropathology and gut microbiota through suppressing C/EBPβ/AEP pathway. J. Neuroinflammation 2023 20 1 19 10.1186/s12974‑023‑02704‑1 36717922
    [Google Scholar]
  121. Zhou Y. Sun Y.-T. Guo H. Liang Y.-Z. Zhu S-.Y. Sha Y. Combination of p-Coumaric acid and lactoferrin ameliorates cognitive deficits through suppressing C/EBPβ/AEP pathway and modulating intestinal flora in APP/PS1 mice. Food Science and Human Wellness 1 20
    [Google Scholar]
  122. Calugi L. Lenci E. Bianchini F. Contini A. Trabocchi A. Modular synthesis of 2,4-diaminoanilines as CNS drug-like non-covalent inhibitors of asparagine endopeptidase. Bioorg. Med. Chem. 2022 63 116746 10.1016/j.bmc.2022.116746 35430537
    [Google Scholar]
  123. Qian Z. Li B. Meng X. Liao J. Wang G. Li Y. Luo Q. Ye K. Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer’s disease in mice. Neuropsychopharmacology 2024 49 3 620 630 10.1038/s41386‑023‑01774‑2 38030711
    [Google Scholar]
  124. Krummenacher D. He W. Kuhn B. Schnider C. Beurier A. Brom V. Sivasothy T. Marty C. Tosstorff A. Hewings D.S. Mesch S. Pinard E. Brändlin M. Hochstrasser R. Westwood P. Rothe J. Kronenberger A. Morandi F. Gutbier S. Schuler A. Heer D. Gloria L.E. Joedicke L. Rudolph M.G. Müller L. Grüninger F. Baumann K. Kaniyappan S. Manevski N. Bartels B. Discovery of orally available and brain penetrant AEP inhibitors. J. Med. Chem. 2023 66 24 17026 17043 10.1021/acs.jmedchem.3c01804 38090813
    [Google Scholar]
  125. Wang J. Hu H.J. Liu Z.K. Liu J.J. Wang S.S. Cheng Q. Chen H.Z. Song M. Pharmacological inhibition of asparaginyl endopeptidase by δ-secretase inhibitor 11 mitigates Alzheimer’s disease-related pathologies in a senescence-accelerated mouse model. Transl. Neurodegener. 2021 10 1 12 10.1186/s40035‑021‑00235‑4 33789744
    [Google Scholar]
  126. Liu C. Liu Z. Fang Y. Du Z. Yan Z. Yuan X. Dai L. Yu T. Xiong M. Tian Y. Li H. Li F. Zhang J. Meng L. Wang Z. Jiang H. Zhang Z. Exposure to the environmentally toxic pesticide maneb induces Parkinson’s disease-like neurotoxicity in mice: A combined proteomic and metabolomic analysis. Chemosphere 2022 308 Pt 2 136344 10.1016/j.chemosphere.2022.136344 36087732
    [Google Scholar]
  127. Mi X. Du H. Guo X. Wu Y. Shen L. Luo Y. Wang D. Su Q. Xiang R. Yue S. Wu S. Gong J. Yang Z. Zhang Y. Tan X. Asparagine endopeptidase-targeted ultrasound-responsive nanobubbles alleviate Tau cleavage and Amyloid-β deposition in an Alzheimer’s disease model. Acta Biomater. 2022 141 388 397 10.1016/j.actbio.2022.01.023 35045359
    [Google Scholar]
  128. Qi Q. Obianyo O. Du Y. Fu H. Li S. Ye K. Blockade of asparagine endopeptidase inhibits cancer metastasis. J. Med. Chem. 2017 60 17 7244 7255 10.1021/acs.jmedchem.7b00228 28820254
    [Google Scholar]
  129. Edgington-Mitchell L.E. Wartmann T. Fleming A.K. Gocheva V. van der Linden W.A. Withana N.P. Verdoes M. Aurelio L. Edgington-Mitchell D. Lieu T. Parker B.S. Graham B. Reinheckel T. Furness J.B. Joyce J.A. Storz P. Halangk W. Bogyo M. Bunnett N.W. Legumain is activated in macrophages during pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2016 311 3 G548 G560 10.1152/ajpgi.00047.2016 27514475
    [Google Scholar]
  130. Chen J. Xu W. Song K. Da L.T. Zhang X. Lin M. Hong X. Zhang S. Guo F. Legumain inhibitor prevents breast cancer bone metastasis by attenuating osteoclast differentiation and function. Bone 2023 169 116680 10.1016/j.bone.2023.116680 36702335
    [Google Scholar]
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