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Cited by 31Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsPeripheral Neuropathies and Disorders

Phosphorylated α-synuclein aggregated in Schwann cells exacerbates peripheral neuroinflammation and nerve dysfunction in Parkinson’s disease through TLR2/NF-κB pathway

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Sun, Li, Jiang, Wen-Wen, Wang, Ye, Yuan, Yong-Sheng, Rong, Zhe, Wu, Jing, Fan, Yi, Lu, Ming +1 more·2021·Cell Death Discovery
DOI 10.1038/s41420-021-00676-wPMC PMC8511120
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Abstract

To investigate the mechanism of peripheral neuropathy in Parkinson’s disease (PD), we prepared a PD mice model by long-term exposure of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mimic PD pathology in humans and the sciatic nerves were taken for further research. It turned out that phosphorylated α-synuclein (p-α-syn) was significantly deposited in Schwann cells (SCs) of sciatic nerves possibly contributing to degenerated myelin SCs and atrophied axons in MPTP group. Further analysis confirmed that toll-like receptors (TLRs) were implicated with PD peripheral neuropathy, in which TLR2 exhibits the predominant expression. Increased expression of inflammatory factors about TLR2/nuclear factor kappa-B (NF-κB) pathway was noted in MPTP group compared to saline group, with proteins on other pathways showing no changes. Moreover, MPTP-challenged mice exhibited worse motor ability and damaged nerve conduction, implicating that p-α-syn neurotoxicity might be relevant to impairments of motor and sensory nerves. After the treatment of CU-CPT22, a TLR2 antagonist, p-α-syn accumulation, motor and sensory function were ameliorated in CU-CPT22 combined with MPTP group. Thus, we demonstrated that pathological p-α-syn might combine TLR2 to affect SCs activation, inflammatory response as well as motor and sensory function through TLR2/nuclear factor kappa-B (NF-κB) signaling pathway. This study firstly demonstrates a novel mechanism of p-α-syn accumulated in SCs of peripheral nerves, which extends our understanding on SCs-mediated peripheral neuroinflammation related to TLR2/NF-κB signaling pathway and sheds light on potential new therapeutic avenues for PD.

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  • CU-CPT22, a small molecule that specifically inhibits TLR1 and TLR2 receptors, reduced activation of NF-κB pathway and secretion of IL-1β and TNF-α in vitro, and ameliorated motor and sensory function in MPTP-induced PD mouse model in vivo.

    “CU-CPT22, a small molecule that specifically inhibits TLR1 and TLR2 receptors, reduced activation of the NF-κB pathway and secretion of the proinflammatory cytokines IL-1β and TNF-α in vitro,567 as well as ameliorated motor and sensory function in MPTP-induced PD mouse model in vivo.568”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [568]

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Research works printed but not linked: 49

  1. [1]Burré J Sharma M Sudhof TC Cell biology and pathophysiology of alpha-synuclein Cold Spring Harb Perspect Med 2018 8 a024091 10.1101/cshperspect.a024091 28108534 PMC5519445 · DOI
  2. [2]Pang SY Ho PW Liu HF Leung CT Li L Chang EES The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson’s disease Transl Neurodegener 2019 8 23 10.1186/s40035-019-0165-9 31428316 PMC6696688 · DOI
  3. [3]Arawaka S Sato H Sasaki A Koyama S Kato T Mechanisms underlying extensive Ser129-phosphorylation in alpha-synuclein aggregates Acta Neuropathol Commun 2017 5 48 10.1186/s40478-017-0452-6 28619113 PMC5472914 · DOI
  4. [4]Killinger BA Melki R Brundin P Kordower JH Endogenous alpha-synuclein monomers, oligomers and resulting pathology: let’s talk about the lipids in the room NPJ Parkinsons Dis 2019 5 23 10.1038/s41531-019-0095-3 31728405 PMC6851126 · DOI
  5. [5]Fenyi A Leclair-Visonneau L Clairembault T Coron E Neunlist M Melki R Detection of alpha-synuclein aggregates in gastrointestinal biopsies by protein misfolding cyclic amplification Neurobiol Dis 2019 129 38 43 10.1016/j.nbd.2019.05.002 31078683 · DOI
  6. [6]Malek N Swallow D Grosset KA Anichtchik O Spillantini M Grosset DG Alpha-synuclein in peripheral tissues and body fluids as a biomarker for Parkinson’s disease-a systematic review Acta Neurol Scand 2014 130 59 72 10.1111/ane.12247 24702516 · DOI
  7. [7]Mammadova N Summers CM Kokemuller RD He Q Ding S Baron T Accelerated accumulation of retinal alpha-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson’s disease Neurobiol Dis 2019 121 1 16 10.1016/j.nbd.2018.09.013 30218757 · DOI
  8. [8]Ortuno-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phosphorylated alpha-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity Mov Disord 2018 33 1315 24 10.1002/mds.27392 29737566 PMC6146055 · DOI
  9. [9]Sumikura H Takao M Hatsuta H Ito S Nakano Y Uchino A Distribution of alpha-synuclein in the spinal cord and dorsal root ganglia in an autopsy cohort of elderly persons Acta Neuropathol Commun 2015 3 57 10.1186/s40478-015-0236-9 26374630 PMC4571135 · DOI
  10. [10]Rocha EM De Miranda B Sanders LH Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease Neurobiol Dis 2018 109 249 57 10.1016/j.nbd.2017.04.004 28400134 · DOI
  11. [11]Beier EE Neal M Alam G Edler M Wu LJ Richardson JR Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide Neurobiol Dis 2017 108 115 127 10.1016/j.nbd.2017.08.009 28823928 PMC5734673 · DOI
  12. [13]Ugalde-Muniz P Fetter-Pruneda I Navarro L Garcia E Chavarria A Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model Oxid Med Cell Longev 2020 2020 4807179 10.1155/2020/4807179 32015787 PMC6982359 · DOI
  13. [14]Zhang H Wu J Shen FF Yuan YS Li X Ji P Activated Schwann cells and increased inflammatory cytokines IL-1beta, IL-6, and TNF-alpha in patients’ sural nerve are lack of tight relationship with specific sensory disturbances in Parkinson’s disease CNS Neurosci Ther 2020 26 518 26 10.1111/cns.13282 31828965 PMC7163790 · DOI
  14. [15]Ydens E Lornet G Smits V Goethals S Timmerman V Janssens S The neuroinflammatory role of Schwann cells in disease Neurobiol Dis 2013 55 95 103 10.1016/j.nbd.2013.03.005 23523637 · DOI
  15. [16]Carr MJ Johnston AP Schwann cells as drivers of tissue repair and regeneration Curr Opin Neurobiol 2017 47 52 7 10.1016/j.conb.2017.09.003 28963968 · DOI
  16. [18]Lee Y Lee S Chang SC Lee J Significant roles of neuroinflammation in Parkinson’s disease: therapeutic targets for PD prevention Arch Pharm Res 2019 42 416 25 10.1007/s12272-019-01133-0 30830660 · DOI
  17. [19]Goncalves NP Vaegter CB Andersen H Ostergaard L Calcutt NA Jensen TS Schwann cell interactions with axons and microvessels in diabetic neuropathy Nat Rev Neurol 2017 13 135 147 10.1038/nrneurol.2016.201 28134254 PMC7391875 · DOI
  18. [20]De Virgilio A Greco A Fabbrini G Inghilleri M Rizzo MI Gallo A Parkinson’s disease: autoimmunity and neuroinflammation Autoimmun Rev 2016 15 1005 1011 10.1016/j.autrev.2016.07.022 27497913 · DOI
  19. [21]Phani S Loike JD Przedborski S Neurodegeneration and Inflammation in Parkinson’s disease Parkinsonism Relat Disord 2012 18 S207 09 10.1016/S1353-8020(11)70064-5 22166436 · DOI · Paper page
  20. [22]Wang Q Liu Y Zhou J Neuroinflammation in Parkinson’s disease and its potential as therapeutic target Transl Neurodegener 2015 4 19 10.1186/s40035-015-0042-0 26464797 PMC4603346 · DOI · Paper page
  21. [23]Tsukita K Sakamaki-Tsukita H Tanaka K Suenaga T Takahashi R Value of in vivo alpha-synuclein deposits in Parkinson’s disease: a systematic review and meta-analysis Mov Disord. 2019 34 1452 63 10.1002/mds.27794 31322768 · DOI
  22. [24]Zhang H Zhu L Sun L Zhi Y Ding J Yuan YS Phosphorylated alpha-synuclein deposits in sural nerve deriving from Schwann cells: a biomarker for Parkinson’s disease Parkinsonism Relat Disord 2019 60 57 63 10.1016/j.parkreldis.2018.10.003 30297212 · DOI
  23. [25]Park HT Kim YH Lee KE Kim JK Behind the pathology of macrophage-associated demyelination in inflammatory neuropathies: demyelinating Schwann cells Cell Mol Life Sci 2020 77 2497 2506 10.1007/s00018-019-03431-8 31884566 PMC7320037 · DOI
  24. [26]Chu LW Cheng KI Chen JY Cheng YC Chang YC Yeh JL Loganin prevents chronic constriction injury-provoked neuropathic pain by reducing TNF-alpha/IL-1beta-mediated NF-kappaB activation and Schwann cell demyelination Phytomedicine 2020 67 153166 10.1016/j.phymed.2019.153166 31955133 · DOI
  25. [27]La Vitola P Balducci C Baroni M Artioli L Santamaria G Castiglioni M Peripheral inflammation exacerbates alpha-synuclein toxicity and neuropathology in Parkinson’s models Neuropathol Appl Neurobiol 2021 47 43 60 10.1111/nan.12644 32696999 · DOI
  26. [28]Koo JH Jang YC Hwang DJ Um HS Lee NH Jung JH Treadmill exercise produces neuroprotective effects in a murine model of Parkinson’s disease by regulating the TLR2/MyD88/NF-kappaB signaling pathway Neuroscience 2017 356 102 113 10.1016/j.neuroscience.2017.05.016 28527958 · DOI
  27. [30]Daniele SG Beraud D Davenport C Cheng K Yin H Maguire-Zeiss KA Activation of MyD88-dependent TLR1/2 signaling by misfolded alpha-synuclein, a protein linked to neurodegenerative disorders Sci Signal 2015 8 ra45 10.1126/scisignal.2005965 25969543 PMC4601639 · DOI · Paper page
  28. [32]Dzamko N Gysbers A Perera G Bahar A Shankar A Gao J Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology Acta Neuropathol 2017 133 303 19 10.1007/s00401-016-1648-8 27888296 PMC5250664 · DOI · Paper page
  29. [33]Hoffmann O Braun JS Becker D Halle A Freyer D Dagand E TLR2 mediates neuroinflammation and neuronal damage J Immunol 2007 178 6476 81 10.4049/jimmunol.178.10.6476 17475877 · DOI
  30. [34]Kim C Spencer B Rockenstein E Yamakado H Mante M Adame A Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating alpha-synuclein transmission and neuroinflammation Mol Neurodegener 2018 13 43 10.1186/s13024-018-0276-2 30092810 PMC6085656 · DOI · Paper page
  31. [35]Caputi V, Giron MC. Microbiome-gut-brain axis and toll-like receptors in Parkinson’s disease. Int J Mol Sci. 2018;19:1689. PMC6032048 29882798
  32. [36]Bellucci A Bubacco L Longhena F Parrella E Faustini G Porrini V Nuclear factor-kappaB dysregulation and alpha-synuclein pathology: critical interplay in the pathogenesis of Parkinson’s disease Front Aging Neurosci 2020 12 68 10.3389/fnagi.2020.00068 32265684 PMC7105602 · DOI
  33. [37]Goethals S Ydens E Timmerman V Janssens S Toll-like receptor expression in the peripheral nerve Glia 2010 58 1701 09 10.1002/glia.21041 20578041 · DOI
  34. [39]Boyko AA, Troyanova NI, Kovalenko EI, Sapozhnikov AM. Similarity and differences in inflammation-related characteristics of the peripheral immune system of patients with Parkinson’s and Alzheimer’s diseases. Int J Mol Sci. 2017;18:2633. PMC5751236 29211044
  35. [40]Yan X, Liu DF, Zhang XY, Liu D, Xu SY, Chen GX, et al. Vanillin protects dopaminergic neurons against inflammation-mediated cell death by inhibiting ERK1/2, P38 and the NF-kappaB signaling pathway. Int J Mol Sci. 2017;18:389. PMC5343924 28208679
  36. [41]Vitola PL Balducci C Cerovic M Santamaria G Brandi E Grandi F Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2 Brain Behav Immun 2018 69 591 602 10.1016/j.bbi.2018.02.012 29458199 · DOI
  37. [42]Lin F Shan W Zheng Y Pan L Zuo Z Toll-like receptor 2 activation and up-regulation by high mobility group box-1 contribute to post-operative neuroinflammation and cognitive dysfunction in mice J Neurochem. 2021 158 328 41 10.1111/jnc.15368 33871050 PMC8895530 · DOI
  38. [43]Wang PH Tsai CL Wu KC Shao CJ Kuo LC Jou IM Effects of different dosage of dexamethasone on behavioral, electrophysiological, and histomorphological recovery in a chronic sciatic nerve compression model Pain Med 2015 16 765 76 10.1111/pme.12680 25586524 · DOI
  39. [44]Abdolmaleki A Zahri S Bayrami A Rosuvastatin enhanced functional recovery after sciatic nerve injury in the rat Eur J Pharm 2020 882 173260 10.1016/j.ejphar.2020.173260 32534070 · DOI
  40. [45]Kim S Kwon SH Kam TI Panicker N Karuppagounder SS Lee S Transneuronal propagation of pathologic alpha-synuclein from the gut to the brain models Parkinson’s disease Neuron 2019 103 627 41 e627 10.1016/j.neuron.2019.05.035 31255487 PMC6706297 · DOI · Paper page
  41. [46]Arotcarena ML Dovero S Prigent A Bourdenx M Camus S Porras G Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates Brain 2020 143 1462 75 10.1093/brain/awaa096 32380543 · DOI · Paper page
  42. [47]Guo C Zhu J Wang J Duan J Ma S Yin Y Neuroprotective effects of rotocatechuic aldehyde through PLK2/p-GSK3β/Nrf2 signaling pathway in both in vivo and in vitro models of Parkinson’s disease Aging 2019 11 9424 41 10.18632/aging.102394 31697645 PMC6874433 · DOI
  43. [49]Bruna J Udina E Ale A Vilches JJ Vynckier A Monbaliu J Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice Exp Neurol 2010 223 599 608 10.1016/j.expneurol.2010.02.006 20188093 · DOI
  44. [50]Uceyler N Kobsar I Biko L Ulzheimer J Levinson SR Martini R Heterozygous P0 deficiency protects mice from vincristine-induced polyneuropathy J Neurosci Res 2006 84 37 46 10.1002/jnr.20873 16676325 · DOI
  45. [51]Taylan SB Bariskaner H Effects of dexmedetomidine and dexketoprofen on the conduction block of rat sciatic nerve Neural Regen Res 2020 15 929 35 10.4103/1673-5374.268926 31719259 PMC6990790 · DOI
  46. [52]Zhou Y Lu M Du RH Qiao C Jiang CY Zhang KZ MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson’s disease Mol Neurodegener 2016 11 28 10.1186/s13024-016-0094-3 27084336 PMC4833896 · DOI · Paper page
  47. [53]Jia M Li C Zheng Y Ding X Chen M Ding J Leonurine exerts antidepressant-like effects in the chronic mild stress-induced depression model in mice by inhibiting neuroinflammation Int J Neuropsychopharmacol 2017 20 886 95 10.1093/ijnp/pyx062 29016795 PMC5737563 · DOI
  48. [54]Liang X, Pan J, Cao C, Zhang L, Zhao Y, Fan Y, et al. Transcriptional response of subcutaneous white adipose tissue to acute cold exposure in mice. Int J Mol Sci. 2019;20:3968. PMC6720191 31443159
  49. [55]Zhu J Hu Z Han X Wang D Jiang Q Ding J Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of beta-arrestin2 and NLRP3 Cell Death Differ 2018 25 2037 49 10.1038/s41418-018-0127-2 29786071 PMC6219479 · DOI

Cited by

Sorted by citations

Authors
Sun, L., Jiang, W.-W., Wang, Y., Yuan, Y.-S., Rong, Z., Wu, J., Fan, Y., Lu, M., & Zhang, K.-Z.
Affiliations
  • Jiangsu Province Hospital (CN)
  • Nanjing Medical University (CN)
Corresponding author
Lu, Ming
ORCID
Venue
Cell Death Discovery
Publisher
Springer Science and Business Media LLC
Published
2021-10-12
Volume
7
Issue
1
Pages
289-289
ISSN
2058-7716 (ISSN-L)
DOI
10.1038/s41420-021-00676-w
PMC
PMC8511120
OpenAlex
W3206460119
Cited by
31
References
6
Citations by year
2026: 5 · 2025: 8 · 2024: 8 · 2023: 5 · 2022: 5
FWCI
2.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death Discovery (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (82071431)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
Keywords
Parkinson's disease, phosphorylated alpha-synuclein, Schwann cells, peripheral neuropathy, TLR2, NF-κB signaling, MPTP mouse model, sciatic nerve, myelin degeneration, axonal atrophy, nerve conduction, sensorimotor function, neuroinflammation

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