研究生: |
楊佩寧 Yang, Pei-Ning |
---|---|
論文名稱: |
針對帕金森氏症探討神經性發炎致病機制與具有淺力的治療策略 Parkinson’s disease: investigation of pathogenic mechanism and therapeutic strategy of neuroinflammation |
指導教授: |
李桂楨
Lee, Guey-Jen |
學位類別: |
碩士 Master |
系所名稱: |
生命科學系 Department of Life Science |
論文出版年: | 2020 |
畢業學年度: | 108 |
語文別: | 中文 |
論文頁數: | 96 |
中文關鍵詞: | 帕金森氏症 、神經炎症 、發炎體 、BV-2微膠細胞 、α-突觸核蛋白 、BE(2)-M17細胞 、治療策略 |
英文關鍵詞: | Parkinson’s disease, Neuroinflammation, Inflammasome, BV-2 microglia, α-Synuclein, BE(2)-M17 cell model, Therapeutics |
DOI URL: | http://doi.org/10.6345/NTNU202001600 |
論文種類: | 學術論文 |
相關次數: | 點閱:192 下載:0 |
分享至: |
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報 |
帕金森氏症(Parkinson’s disease)為一種漸進性神經退化疾病,在全球60歲以上的族群中約有1%的人患有此疾病。臨床上,大多數患者顯示出黑質緻密部中多巴胺能神經元的缺失和α-突觸核蛋白(α-Synuclein)的存在,引起運動遲緩、靜息性震顫、僵硬和體位不穩等主要症狀。α-突觸核蛋白本質上是一種非結構化蛋白質,易形成不溶性原纖維和聚集體。最近研究顯示,大腦中的微膠細胞(Microglia)介導的免疫反應積極促進了PD的發病機制,而細胞外α-突觸核蛋白促進了微膠細胞的發炎反應。本研究首先利用原核生物生產的帶有His標籤的α-突觸核蛋白,在37°C下連續搖動三天後,形成α-突觸核蛋白原纖維。用α-突觸核蛋白原纖維刺激小鼠BV-2微膠細胞20小時後,觀察到一氧化氮(NO)和Iba-1的產量增加,且激活的微膠細胞伸長且突起延長。接著利用α-突觸核蛋白原纖維激活BV-2,檢測七種化合物的抗發炎性,包括C12-HSL、3-oxo-C12-HSL (兩種N-酰基高絲氨酸內酯)、7-Chlorokynurenic acid (7-Cl-KYNA,一非競爭型NMDA受體拮抗劑)、4-Chlorokynurenine (4-Cl-KYN,一穿透腦的7-Cl-KYNA前驅藥)、LM-031、LM-021 (兩種查爾酮-香豆素衍生物)和NC009-1 (一種吲哚化合物)等,藉檢測上述化合物前處理的BV-2培養液中NO以及M1 (IL-1β、IL-6、TNF-α)和M2 (IL-4、IL-10、TGF-β)細胞激素的水平,來評估化合物的抗炎潛能。NO和細胞激素ELISA分析結果顯示,α-突觸核蛋白原纖維誘導發炎的BV-2細胞培養液中,NO、IL-1β、IL-6和TNF-α的表達增加,而LM-021和NC009-1預處理可有效降低了上述促炎介質的表達和釋放。為進一步檢查LM-021和NC009-1對帕金森氏症的治療潛力,本研究建立視黃酸(Retinoic acid)誘導神經分化、誘導表達A53T α-突觸核蛋白-GFP及α-突觸核蛋白原纖維依存的神經細胞瘤BE(2)-M17細胞。上述細胞前處理LM-021和NC009-1後,誘導A53T α-突觸核蛋白-GFP表現並加入α-突觸核蛋白原纖維,六天後評估LM-021和NC009-1促進神經突生長情形,並藉點轉漬法來評估抑制α-突觸核蛋白聚集形成的抗炎潛能。結果顯示NC009-1可以促進神經突生長及抑制α-突觸核蛋白聚集,LM-021改善神經突生長雖然未達顯著性,但可抑制α-突觸核蛋白聚集。這項研究提供了新的應用觀點,以有益於α-突觸核蛋白刺激的帕金森氏症神經炎症的藥物開發。
Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder that is estimated to affect approximately 1% of the population older than 60 years of age. Clinically, most patients present with the cardinal symptoms of bradykinesia, resting tremor, rigidity and postural instability that are induced by the loss of dopaminergic neurons in substantia nigra compacta and the presence of α-synuclein containing Lewy bodies. α-Synuclein is an intrinsically unstructured protein prone to forming insoluble fibrils and aggregates. Recently, it is becoming evident that microglia-mediated immune responses in the brain actively contribute to the pathogenesis of PD and extracellular α-synuclein increases the production of pro-inflammatory mediators in microglia. In this study, prokaryotic-derived His-tagged α-synuclein was incubated at 37°C with continuous shaking for 3 days to form α-synuclein fibrils. After stimulation of mouse BV-2 microglial cells with the preformed α-synuclein fibrils for 20 h, increased production of nitric oxide (NO) and induction of brown adipocytes 1 (Iba-1) was observed and the activated microglia became elongated with extended processes. In the present study, seven compounds including C12-HSL, 3-oxo-C12-HSL (two N-Acyl homoserine lactones), 7-chlorokynurenic acid (a noncompetitive NMDA receptor antagonist), 4-chlorokynurenine (a brain-penetrant prodrug of 7-chlorokynurenic acid), LM-031, LM-021 (two in-house chalcone-coumarin derivatives), and NC009-1 (an indole compound) were tested for the anti-inflammatory effects on α-synuclein-induced inflammation. The anti-inflammatory potentials of these compounds were assessed by examination of NO as well as M1 (IL-1β, IL-6, TNF-α) and M2 (IL-4, IL-10, TGF-β) cytokine levels in cultured medium collected from α-synuclein-activated BV-2 cells with or without compound pretreatment. NO and cytokine ELISA assays revealed increased expression of NO, IL-1β, IL-6 and TNF-α in α-synuclein-inflamed BV-2 cells, and LM-021 and NC009-1 pretreatment effectively reduced the expression and release of these pro-inflammatory mediators. To examine the therapeutic potential of LM-021 and NC009-1 in PD, retinoic acid (a metabolite of vitamin A) differentiated human neuroblastoma BE(2)-M17 cells with inducible A53T α-synuclein-GFP expression and α-synuclein fibril-dependent aggregate formation were established. After LM-021 and NC009-1 pretreatment, A53T α-synuclein-GFP induction and α-synuclein fibrils addition for 6 days, neurite outgrowth promotion and α-synuclein aggregate inhibition (by dot blot) were evaluated. The results demonstrated that NC009-1 promoted neurite outgrowth and inhibited α-synuclein aggregation. Although improvement of neurite growth was not significant, LM-021 inhibited α-synuclein aggregation. The study offers new viewpoints of application to benefit drug development for α-synuclein-stimulated neuroinflammation in PD.
顏阡聿, 2019. 抗發炎相關化合物VB-037及甘草次酸在帕金森氏症細胞模式上之治療潛力.
Andres D , Keyser BM, Petrali J, Benton B, Hubbard KS, McNutt PM, Ray R. 2013. Morphological and functional differentiation in BE(2)-M17 human neuroblastoma cells by treatment with Trans-retinoic acid. BMC Neurosci. 14:49.
Ahn BH, Rhim H, Kim SY, Sung YM, Lee MY, Choi JY, Wolozin B, Chang JS, Lee YH, Kwon TK, Chung KC, Yoon SH, Hahn SJ, Kim MS, Jo YH, Min DS. 2002. α-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells. J Biol Chem. 277:12334-12342.
Alerte TN, Akinfolarin AA, Friedrich EE, Mader SA, Hong CS, Perez RG. 2008. α-Synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: lessons from viral transduction of knockout mice. Neurosci Lett. 435:24-29.
Beraud D, Twomey M, Bloom B, Mittereder A, Ton V, Neitzke K, Chasovskikh S, Mhyre TR, Maguire-Zeiss KA. 2011. α-Synuclein alters toll-like receptor expression. Front Neurosci. 5:80.
Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F. 1990. Immortalization of murine microglial cells by a v-raf / v-myc carrying retrovirus. J Neuroimmunol. 27:229-237.
Blum-Degen D, Müller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. 1995. Interleukin-1β and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett. 202:17-20.
Brieger K, Schiavone S, Miller Jr FJ, Krause KH. 2012. Reactive oxygen species: from health to disease. Swiss Medical Weekly. 42: 13659.
Brucale M, Sandal M, Di Maio S, Rampioni A, Tessari I, Tosatto L, Bisaglia M, Bubacco L, Samorì B. 2009. Pathogenic mutations shift the equilibria of α-synuclein single molecules towards structured conformers. Chembiochem. 10:176-183.
Bruce-Keller AJ. 1999. Microglial–neuronal interactions in synaptic damage and recovery. J Neurosci Res. 58:191-201.
Busquets O, Ettcheto M, Verdaguer E, Castro-Torres RD, Auladell C, Beas-Zarate C, Folch J, Camins A. 2018. JNK1 inhibition by Licochalcone A leads to neuronal protection against excitotoxic insults derived of kainic acid. Neuropharmacology. 131:440-452.
Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M. 2005. Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Neurosci. 29:381-393.
Burre, J. 2015. The synaptic function of α-synuclein. J. Parkinsons. Dis. 5:699-713.
Bussell JR, Eliezer D. 2001. Residual structure and dynamics in Parkinson’s disease-associated mutants of α-synuclein. J Biol Chem. 276(49):45996-6003.
Chang KH, Chiu YJ, Chen SL, Huang CH, Lin CH, Lin TH, Lee CM, Ramesh C, Wu CH, Huang CC, Fung HC, Chen YC, Lin JY, Yao CF, Huang HJ, Lee-Chen GJ, Lee MC, Hsieh-Li HM. 2016. The potential of synthetic indolylquinoline derivatives for Aβ aggregation reduction by chemical chaperone activity. Neuropharmacology. 101:309-319.
Chang KH, Lin CH, Chen HC, Huang HY, Chen SL, Lin TH, Ramesh C, Huang CC, Fung HC, Wu YR, Huang HJ, Lee-Chen GJ, Hsieh-Li HM, Yao CF. 2017. The potential of indole/indolylquinoline compounds in tau misfolding reduction by enhancement of HSPB1. CNS Neurosci Ther. 23(1):45-56.
Chapman V, Dickenson AH. 1995. Time-related roles of excitatory amino acid receptors during persistent noxiously evoked responses of rat dorsal horn neurones. Brain Res. 703:45-50.
Chen CM, Chen WL, Hung CT, Lin TH, Chao CY, Lin CH, Wu YR, Chang KH, Yao CF, Lee-Chen GJ, Su MT, Hsieh-Li HM. 2018. The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice. Neurotoxicology. 67:259-269.
Chen YC, Chiu YJ, Lin CH, Hsu WC, Wu JL, Huang CH, Lin CW, Yao CF, Huang HJ, Lo YS, Chen CM, Wu YR, Chang KH, Lee-Chen GJ, Mei Hsieh-Li H. 2019. Indole compound NC009-1 augments APOE and TRKA in Alzheimer’s disease cell and mouse models for neuroprotection and cognitive improvement. J Alzheimers Dis. 67:737-756.
Cho BP, Song DY, Sugama S, Shin DH, Shimizu Y, Kim SS, Kim YS, Joh TH. 2006. Pathological dynamics of activated microglia following medial forebrain bundle transection. Glia. 53: 92-102.
Clayton DF, George JM. 1999. Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res. 58:120-129.
Coskuner O, Wise-Scira O. 2013. Structures and free energy landscapes of the A53T mutant-type α synuclein protein and impact of A53T mutation on the structures of the wild-type α synuclein protein with dynamics. ACS Chem Neurosci. 4:1101-1113.
Conway KA, Harper JD, Lansbury RT. 1998. Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease. Nat Med. 4:1318-1320.
Codolo G, Plotegher N, Pozzobon T, Brucale M, Tessari I, Bubacco L, Bernard MD. 2013. Triggering of inflammasome by aggregated α–synuclein, an inflammatory response in synucleinopathies. PLoS One. 8:e55375.
Croisier E, Moran LB, Dexter DT, Pearce RK, Graeber MB. 2005. Microglial inflammation in the parkinsonian substantia nigra: relationship to α-synuclein deposition. J Neuroinflammation. 2:14.
de Zoete MR, Palm NW, Zhu S, Flavell RA. 2014. Inflammasomes. Cold Spring Harb Perspect Biol. 6:a016287.
Dheen ST, Kaur C, Ling EA. 2007. Microglial activation and its implications in the brain diseases. Curr Med Chem. 14:1189-1197.
Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK, Litvan I. 2009. Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol. 8:1150-1157.
Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, Marshall FJ, Ravina BM, Schifitto G, Siderowf A, Tanner CM. 2007. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 68:384-386.
Edvardson S, Cinnamon Y, Ta-Shma A, Shaag A, Yim YI, Zenvirt S, Jalas C, Lesage S, Brice A, Taraboulos A, Kaestner KH, Greene LE, Elpeleg O. 2012. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLoS One. 7:e36458.
Emamzadeh FN. 2016. α-Synuclein structure, functions, and interactions. J Res Med Sci. 21:29.
Elbein AD, Pan YT, Pastuszak I, Carroll D. 2003. New insights on trehalose: a multifunctional molecule. Glycobiology. 13:17R-27R.
Eriksen JL, Wszolek Z, Petrucelli L. 2005. Molecular pathogenesis of Parkinson disease. Neurol. 62:353-357.
Fahn S. 2003. Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci. 991:1-14.
Filograna R, Civiero L, Ferrari V, Codolo G, Greggio E, Bubacco L, Beltramini M, Bisaglia M. 2015. Analysis of the catecholaminergic phenotype in human SH-SY5Y and BE(2)-M17 neuroblastoma cell lines upon differentiation. PLoS One. 10:e0136769.
Furusawa J, Funakoshi-Tago M, Mashino T, Tago K, Inoue H, Sonoda Y, Kasahara T. 2009. Glycyrrhiza inflata-derived chalcones, Licochalcone A, Licochalcone B and Licochalcone D, inhibit phosphorylation of NF-κB p65 in LPS signaling pathway. Int Immunopharmacol. 9:499-507.
Gehrmann J, Matsumoto Y, Kreutzberg GW. 1995. Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev. 20:269-287.
Gendron FP, Chalimoniuk M, Strosznajder J, Shen S, González FA, Weisman GA, Sun GY. 2003. P2X7 nucleotide receptor activation enhances IFN gamma-induced type II nitric oxide synthase activity in BV-2 microglial cells. J Neurochem. 87:344-352.
Giasson BI, Murray IV, Trojanowski JQ, Lee VM. 2001. A hydrophobic stretch of 12 amino acid residues in the middle of α-synuclein is essential for filament assembly. J Biol Chem. 276:2380-2386.
Goetz CG. 2011. The history of Parkinson’s disease: early clinical descriptions and neurological therapies. Cold Spring Harb Perspect Med. 1:a008862.
Gordon S, Taylor PR. 2005. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 5:953-964.
Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, Robertson AAB, Butler MS, Rowe DB, O'Neill LA, Kanthasamy AG, Schroder K, Cooper MA, Woodruff TM. 2018. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 10:eaah4066.
Guo JL, Lee VM. 2014. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med. 20: 130-138.
Hain EG, Sparenberg M, Rasińska J, Klein C, Akyüz L, Steiner B. 2018. Indomethacin promotes survival of new neurons in the adult murine hippocampus accompanied by anti-inflammatory effects following MPTP-induced dopamine depletion. J Neuroinflammation. 15:162.
Hanisch UK, Kettenmann H. 2007. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 10:1387-1394.
Haque E, Akther M, Jakaria, Kim IS, Azam S, Choi DK. 2019. Targeting the microglial NLRP3 inflammasome and its role in Parkinson’s disease. Mov Disor. 35:20-33.
He C, Carter AB. 2015. The metabolic prospective and redox regulation of macrophage polarization. J Clin Cell Immunol. 6:371.
Hirsch EC, Hunot S, Hartmann A. 2005. Neuroinflammatory processes in Parkinson’s disease. Parkinsonism Relat Disord. 11(Suppl 1):S9-S15.
Hirsch EC , Vyas S, Hunot S. 2012. Neuroinflammation in Parkinson’s disease. Parkinsonism Relat Disord. 18 Suppl 1:S210-212.
Hitchcock SA, Pennington LD. 2006. Structure - brain exposure relationships. J Med Chem. 49:7559-7583.
Hochstrasser T, Hohsfield LA, Sperner-Unterweger B, Humpel C. 2013. β-Amyloid induced effects on cholinergic, serotonergic, and dopaminergic neurons is differentially counteracted by anti-inflammatory drugs. J Neurosci Res. 91:83-94.
Hoehn MM, Yahr MD. 1967. Parkinsonism: onset, progression, and mortality. Neurology. 17:427-442.
Hoffmann A, Ettle B, Bruno A, Kulinich A, Hoffmann AC, von Wittgenstein J, Winkler J, Xiang W, Schlachetzki JCM. 2016. α-Synuclein activates BV2 microglia dependent on its aggregation state. Biochem Biophys Res Commun. 479:881-886.
Hokari M, Wu HQ, Schwarcz R, Smith QR. 1996. Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid. Neuroreport. 8:15-18.
Joshi N, Singh S. 2018. Updates on immunity and inflammation in Parkinson disease pathology. J Neurosci Res. 96:379-390.
Kasten M, Klein C. 2013. The many faces of α-synuclein mutations. Mov Disord. 28:697-701.
Kastner A, Hirsch EC, Agid Y, Javoy-Agid F. 1993. Tyrosine hydroxylase protein and messenger RNA in the dopaminergic nigral neurons of patients with Parkinson’s disease. Brain Res. 606:341-345.
Kaur C, Ling EA, Wong WC. 1985. Transformation of amoeboid microglial cells into microglia in the corpus callosum of the postnatal rat brain. An electron microscopical study. Arch Histol Jpn. 48:17-25.
Kaur C, Ling EA. 1991. Study of the transformation of amoeboid microglial cells into microglia labelled with the isolectin Griffonia simplicifolia in postnatal rats. Acta Anat (Basel). 142:118-125.
Kaur C, Sivakumar V, Foulds WS. 2006. Early response of neurons and glial cells to hypoxia in the retina. Invest Ophthalmol Vis Sci. 47:1126-1141.
Kelder J, Grootenhuis PD, Bayada DM, Delbressine LP, Ploemen JP. 1999. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm Res. 16:1514-1519.
Kemp JA, Foster AC, Leeson PD, Priestley T, Tridgett R, Iversen LL, Woodruff GN. 1988. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc Natl Acad Sci U S A. 85:6547-6550.
Kim WG, Mohney RP, Wilson B, Jeohn GH, Liu B, Hong JS. 2000. Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci. 20:6309-6316.
Klein C, Westenberger A. 2012. Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med. 2:a008888.
Kontogiorgis CA, Xu Y, Hadjipavlou-Litina D, Luo Y. 2007. Coumarin derivatives protection against ROS production in cellular models of Aβ toxicities. Free Radic Res. 41:1168-1180.
Koroglu C, Baysal L, Cetinkaya M, Karasoy H, Tolun A. 2013. DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability. Parkinsonism Relat Disord. 19: 320-324.
Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. 2008. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat. Med. 14:504-506.
Krebs CE, Karkheiran S, Powell JC, Cao M, Makarov V, Darvish H, Di Paolo G, Walker RH, Shahidi GA, Buxbaum JD, De Camilli P, Yue Z, Paisan-Ruiz C. 2013. The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive parkinsonism with generalized seizures. Hum Mutat. 34:1200-1207.
Kreutzberg GW. 1996. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19:312-318.
Landman C, Grill JP, Mallet JM, Marteau P, Humbert L, Le Balc’h E, Maubert MA, Perez K, Chaara W, Brot L, Beaugerie L, Sokol H, Thenet S, Rainteau D, Seksik P, Quévrain E; Saint Antoine IBD Network. 2018. Inter-kingdom effect on epithelial cells of the N-Acyl homoserine lactone 3-oxo-C12: 2, a major quorum-sensing molecule from gut microbiota. PLoS One. 13:e0202587.
Lashuel HA, Overk CR, Oueslati A, Masliah E. 2013. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 14:38-48.
Lavedan, C. 1998. The synuclein family. Genome Res. 8:871-880.
Lee SY, Chiu YJ, Yang SM, Chen CM, Huang CC, Lee-Chen GJ, Lin W, Chang KH. 2018. Novel synthetic chalcone-coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection. CNS Neurosci Ther. 24:1286-1298.
Lee VM, Trojanowski JQ. 2006. Mechanisms of Parkinson’s disease linked to pathological α-synuclein: new targets for drug discovery. Neuron, 52:33-38.
Lee SJ. 2008. Origins and effects of extracellular α-synuclein: implications in Parkinson’s disease. J Mol Neurosci. 34:17-22.
Lee HJ, Suk JE, Bae EJ, LeeJH, Paik SR, Lee SJ. 2008. Assembly-dependent endocytosis and clearance of extracellular α-synuclein. Int J Biochem Cell Biol. 40:1835-1849.
Lee EJ, Woo MS, Moon PG, Baek MC, Choi IY, Kim WK, Junn E, Kim HS. 2010. α-Synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J Immunol. 185:615-623.
Lesage S, Drouet V, Majounie E, Deramecourt V, Jacoupy M, Nicolas A, Cormier-Dequaire F, Hassoun SM, Pujol C, Ciura S, Erpapazoglou Z, Usenko T, Maurage CA, Sahbatou M, Liebau S, Ding J, Bilgic B, Emre M, Erginel-Unaltuna N, Guven G, Tison F, Tranchant C, Vidailhet M, Corvol JC, Krack P, Leutenegger AL, Nalls MA, Hernandez DG, Heutink P, Gibbs JR, Hardy J, Wood NW, Gasser T, Durr A, Deleuze JF, Tazir M, Destée A, Lohmann E, Kabashi E, Singleton A, Corti O, Brice A; French Parkinson’s Disease Genetics Study (PDG); International Parkinson’s Disease Genomics Consortium (IPDGC). 2016. Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent mitophagy. Am J Hum Genet. 98:500-513.
Lin TH, Chiu YJ, Lin CH, Lin CY, Chao CY, Chen YC, Yang SM, Lin W, Hsieh-Li HM, Wu YR, Chang KH, Lee-Chen GJ, Chen CM. 2020. Exploration of multi-target effects of 3-benzoyl-5-hydroxychromen-2-one in Alzheimer’s disease cell and mouse models. Aging Cell. 19(7).
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 23:3-25.
Liu H, Wang L, Lv M, Pei R, Li P, Pei Z, Wang Y, Su W, Xie XQ. 2014a. AlzPlatform: an Alzheimer’s disease domain-specific chemogenomics knowledgebase for polypharmacology and target identification research. J Chem Inf Model. 54:1050-1060.
Liu YC, Zou XB, Chai YF, Yao YM. 2014b. Macrophage polarization in inflammatory diseases. Int J Biol Sci. 10:520-529.
Lu A, Wu H. 2015. Structural mechanisms of inflammasome assembly. FEBS J. 282(3):435-444.
Lugo-Villarino G, Vérollet C, Maridonneau-Parini I, Neyrolles O. 2011. Macrophage polarization: convergence point targeted by Mycobacterium tuberculosis and HIV. Front Immunol. 2:43.
Ma D, Doi Y, Jin S, Li E, Sonobe Y, Takeuchi H, Mizuno T, Suzumura A. 2012. TGF-β induced by interleukin-34-stimulated microglia regulates microglial proliferation and attenuates oligomeric amyloid β neurotoxicity. Neurosci Lett. 529:86-91.
Manocha GD, Floden AM, Puig KL, Nagamoto-Combs K, Scherzer CR, Combs CK. 2017. Defining the contribution of neuroinflammation to Parkinson’s disease in humanized immune system mice. Mol Neurodegener. 12:17.
Marinova-Mutafchieva L, Sadeghian M, Broom L, Davis JB, Medhurst AD, Dexter DT. 2009. Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson’s disease. J Neurochem. 110:966-975.
Marques O, Outeiro TF. 2012. α-Synuclein: from secretion to dysfunction and death. Cell Death Dis. 3:e350.
Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. 2014. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 34:15490-15496.
McGeer PL, Itagaki S, Boyes BE, McGeer EG. 1988. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 38:1285-1291.
Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T. 1994. Tumor necrosis factor-α (TNF-α) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett. 165:208-210.
Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P, Louis JC, Wypych J, Biere AL, Citron M. 1999. Both familial Parkinson’s disease mutations accelerate α-synuclein aggregation. J Biol Chem. 274:9843-9846.
Ojha S, Javed H, Azimullah S, Haque ME. 2016. β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease. Mol. Cell. Biochem. 418:59-70.
Pajouhesh H, Lenz GR. 2005. Medicinal chemical properties of successful central nervous system drugs. NeuroRx. 2:541-553.
Perry VH, Gordon S. 1988. Macrophages and microglia in the nervous system. Trends Neurosci. 11:273-277.
Pisanu A, Lecca D, Mulas G, Wardas J, Simbula G, Spiga S. 2014. Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol Dis. 71:280-291.
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL. 1997. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science. 276:2045-2047.
Quadri M, Fang M, Picillo M, Olgiati S, Breedveld GJ, Graafland J, Wu B, Xu F, Erro R, Amboni M, Pappata S, Quarantelli M, Annesi G, Quattrone A, Chien HF, Barbosa ER; International Parkinsonism Genetics Network, Oostra BA, Barone P, Wang J, Bonifati V. 2013. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset parkinsonism. Hum Mutat. 34:1208-1215.
Rajagopalan S, Andersen JK. 2001. Alpha synuclein aggregation: is it the toxic gain of function responsible for neurodegeneration in Parkinson’s disease? Mech Ageing Dev. 122:1499-1510.
Rémy B, Mion S, Plener L, Elias M, Chabrière E, Daudé D. 2018. Interference in bacterial quorum sensing: a biopharmaceutical perspective. Front Pharmacol. 9:203.
Roberts HL, Brown DR. 2015. Seeking a mechanism for the toxicity of oligomeric α-synuclein. Biomolecules. 5:282-305.
Rodriguez JA, Ivanova MI, Sawaya MR, Cascio D, Reyes FE, Shi D, Sangwan S, Guenther EL, Johnson LM, Zhang M, Jiang L, Arbing MA, Nannenga BL, Hattne J, Whitelegge J, Brewster AS, Messerschmidt M, Boutet S, Sauter NK, Gonen T, Eisenberg DS. 2015. Structure of the toxic core of α-synuclein from invisible crystals. Nature. 525:486-490.
Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias R, Bezard E, Obeso JA. 2009. Initial clinical manifestations of Parkinson’s disease: features and pathophysiological mechanisms. Lancet Neurol. 8:1128-1139.
Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, Zalinski J, Cofield M, Mansukhani L, Willson P, Kogan F. 1993. Clinical trial of indomethacin in Alzheimer’s disease. Neurology. 43:1609-1609.
Saavedra-López E, Roig-Martínez M, Cribaro GP, Casanova PV, Gallego JM, Pérez-Vallés A, Barcia C. 2020. Phagocytic glioblastoma-associated microglia and macrophages populate invading pseudopalisades. Brain Communications. doi:10.1093fcz043.
Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. 2016. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 167:1469-1480.e12.
Sanders LH, Greenamyre JT. 2013. Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radic Biol Med. 62:111-120.
Sawada M, Suzumura A, Hosoya H, Marunouchi T, Nagatsu T. 1999. Interleukin-10 inhibits both production of cytokines and expression of cytokine receptors in microglia. J Neurochem. 72:1466-1471.
Salituro FG, Tomlinson RC, Baron BM, Palfreyman MG, McDonald IA, Schmidt W, Wu HQ, Guidetti P, Schwarcz R. 1994. Enzyme-activated antagonists of the strychnine-insensitive Glycine/NMDA receptor. J Med Chem. 37:334-336.
Schapira AH. 2008. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol. 7:97-109.
Scheiblich H, Roloff F, Singh V, Stangel M, Stern M, Bicker G. 2014. Nitric oxide/cyclic GMP signaling regulates motility of a microglial cell line and primary microglia in vitro. Brain Res. 1564:9-21.
Schroder K, Tschopp J. 2010. The inflammasomes. Cell. 140:821-832.
Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M. 2010. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 7:483-495.
Smith QR, Lockman PR. 2011. Prodrug approaches for central nervous system delivery. In Mannhold R. Kubinyi H, Folkers G (eds.). Prodrugs and Targeted Delivery: Towards Better ADME Properties, Volume 47. John Wiley & Sons. p. 259.
Smeyne RJ, Breckenridge CB, Beck M, Jiao Y, Butt MT, Wolf JC. 2016. Assessment of the effects of MPTP and paraquat on dopaminergic neurons and microglia in the substantia nigra pars compacta of C57BL/6 mice. PLoS One. 11:e0164094.
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. 1997. α-Synuclein in Lewy bodies. Nature. 388:839-840.
Spencer NG, Schilling T, Miralles F, Eder C. 2016. Mechanisms underlying interferon-γ-induced priming of microglial reactive oxygen species production. PLoS One. 11:e0162497.
Stoll G, Jander S, Schroeter M. 2000. Cytokines in CNS disorders: neurotoxicity versus neuroprotection. J Neural Transm Suppl. 59:81-89.
Stypuła G, Kunert-Radek J, Stepień H, Zylińska K, Pawlikowski M. 1996. Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with parkinson’s disease. Neuroimmunomodulation. 3:131-134.
Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K, Federoff HJ. 2008. Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol Aging. 29:1690-1701.
Tao X, Li N, Liu F, Hu Y, Liu J, Zhang YM. 2018. In vitro examination of microglia-neuron crosstalk with BV2 cells, and primary cultures of glia and hypothalamic neurons. Heliyon. 4:e00730.
Tanaka T, Narazaki M, Kishimoto T. 2014. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 6:a016295.
Tyson T, Steiner JA, Brundin P. 2016. Sorting out release, uptake and processing of α-synuclein during prion-like spread of pathology. J. Neurochem. 139(Suppl. 1):275-289.
Uversky VN, Li J, Fink AL. 2001. Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein. A possible molecular NK between Parkinson’s disease and heavy metal exposure. J Biol Chem. 276:44284-44296.
Vécsei L, Szalárdy L, Fülöp F, Toldi J. 2013. Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov. 12:64-82.
Vilariño-Güell C, Rajput A, Milnerwood AJ, Shah B, Szu-Tu C, Trinh J, Yu I, Encarnacion M, Munsie LN, Tapia L, Gustavsson EK, Chou P, Tatarnikov I, Evans DM, Pishotta FT, Volta M, Beccano-Kelly D, Thompson C, Lin MK, Sherman HE, Han HJ, Guenther BL, Wasserman WW, Bernard V, Ross CJ, Appel-Cresswell S, Stoessl AJ, Robinson CA, Dickson DW, Ross OA, Wszolek ZK, Aasly JO, Wu RM, Hentati F, Gibson RA, McPherson PS, Girard M, Rajput M, Rajput AH, Farrer MJ. 2014. DNAJC13 mutations in Parkinson disease. Hum Mol Genet. 23:1794-1801.
Villalta SA, Nguyen HX, Deng B, Gotoh T, Tidball JG. 2009. Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. Hum Mol Genet. 18:482-496.
Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. 2009. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 29:3974-3980.
Wang S, Chu CH, Guo M, Jiang L, Nie H, Zhang W, Wilson B, Yang L, Stewart T, Hong JS, Zhang J. 2016. Identification of a specific α-synuclein peptide (α-Syn 29-40) capable of eliciting microglial superoxide production to damage dopaminergic neurons. J Neuroinflammation. 13:158.
Walsh S, Finn DP, Dowd E. 2011. Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson’s disease in the rat. Neuroscience. 175:251-261.
Whitton PS. 2007. Inflammation as a causative factor in the aetiology of Parkinson’s. disease. Br J Pharmacol. 150:963-976.
Wu HQ, Salituro FG, Schwarcz R. 1997. Enzyme-catalyzed production of the neuroprotective NMDA receptor antagonist 7-chlorokynurenic acid in the rat brain in vivo. Eur J Pharmacol. 319:13-20.
Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C. 2002. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci. 22:1763-1771.
Xia R, Mao ZH. 2012. Progression of motor symptoms in Parkinson’s disease. Neurosci Bull. 28:39-48.
Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong JS, Zhang J. 2005. Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 19:533-542.
Zhang W, Dallas S, Zhang D, Guo JP, Pang H, Wilson B, Miller DS, Chen B, Zhang W, McGeer PL, Hong JS, Zhang J. 2007. Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant α-synuclein. Glia. 55:1178-1188.
Zlokovic BV. 2008. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 57:178-201.
Zuk M, Kulma A, Dymińska L, Szołtysek K, Prescha A, Hanuza J, Szopa J. 2011. Flavonoid engineering of flax potentiate its biotechnological application. BMC Biotechnol. 11:10.