Association of glycogen synthase kinase‑3β with Parkinson's disease (Review)

Li,Da‑Wei; Liu,Zhi‑Qiang; Chen,Wei; Yao,Min; Li,Guang‑Ren

doi:10.3892/mmr.2014.2080

Association of glycogen synthase kinase‑3β with Parkinson's disease (Review)

Authors:
- Da‑Wei Li
- Zhi‑Qiang Liu
- Wei Chen
- Min Yao
- Guang‑Ren Li
View Affiliations

Affiliations: Department of Neurology, Affiliated Hospital of Beihua University, Jilin, Jilin 132000, P.R. China, Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Neurology, The Third Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: March 28, 2014 https://doi.org/10.3892/mmr.2014.2080
Pages: 2043-2050
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glycogen synthase kinase‑3 (GSK‑3) is a pleiotropic serine/threonine protein kinase found in almost all eukaryotes. It is structurally highly conserved and has been identified as a multifaceted enzyme affecting a wide range of biological functions, including gene expression and cellular processes. There are two closely related isoforms of GSK‑3; GSK‑3α and GSK‑3β. The latter appears to play crucial roles in regulating the pathogenesis of diverse diseases, including neurodegenerative disease. The present review focuses on the involvement of this protein in Parkinson's disease (PD), a common neurodegenerative disorder characterized by the gradually progressive and selective loss of dopaminergic neurons, and by intracellular inclusions known as Lewy bodies (LBs) expressed in surviving neurons of the substantia nigra (SN). GSK‑3β is involved in multiple signaling pathways and has several phosphorylation targets. Numerous apoptotic conditions can be facilitated by the GSK‑3β signaling pathways. Studies have shown that GSK‑3β inhibition protects the dopaminergic neurons from various stress‑induced injuries, indicating the involvement of GSK‑3β in PD pathogenesis. However, the underlying mechanisms of the protective effect of GSK‑3β inhibition on dopaminergic neurons in PD is not completely understood. Multiple pathological events have been recognized to be responsible for the loss of dopaminergic neurons in PD, including mitochondrial dysfunction, oxidative stress, protein aggregation and neuroinflammation. The present review stresses the regulatory roles of GSK‑3β in these events and in dopaminergic neuron degeneration, in an attempt to gain an improved understanding of the underlying mechanisms and to provide a potential effective therapeutic target for PD.

View Figures

View References

1	Forno LS: Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol. 55:259–272. 1996.
2	McNaught KS and Olanow CW: Protein aggregation in the pathogenesis of familial and sporadic Parkinson’s disease. Neurobiol Aging. 27:530–545. 2006.
3	Martinez-Vicente M, Talloczy Z, Kaushik S, et al: Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest. 118:777–788. 2008.PubMed/NCBI
4	Keeney PM, Xie J, Capaldi RA and Bennett JP Jr: Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci. 26:5256–5264. 2006.
5	Li DW, Li GR, Lu Y, et al: alpha-lipoic acid protects dopaminergic neurons against MPP+-induced apoptosis by attenuating reactive oxygen species formation. Int J Mol Med. 32:108–114. 2013.PubMed/NCBI
6	Rasola A and Bernardi P: Mitochondrial permeability transition in Ca(²⁺)-dependent apoptosis and necrosis. Cell Calcium. 50:222–233. 2011. View Article : Google Scholar
7	Parker WD Jr, Boyson SJ and Parks JK: Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol. 26:719–723. 1989.
8	Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB and Marsden CD: Mitochondrial complex I deficiency in Parkinson’s disease. Lancet. 1:12691989.
9	Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV and Greenamyre JT: Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci. 3:1301–1306. 2000.
10	Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE and Greenamyre JT: A highly reproducible rotenone model of Parkinson’s disease. Neurobiol Dis. 34:279–290. 2009.PubMed/NCBI
11	Hantraye P, Brouillet E, Ferrante R, et al: Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat Med. 2:1017–1021. 1996. View Article : Google Scholar : PubMed/NCBI
12	Shang T, Kotamraju S, Kalivendi SV, Hillard CJ and Kalyanaraman B: 1-Methyl-4-phenylpyridinium-induced apoptosis in cerebellar granule neurons is mediated by transferrin receptor iron-dependent depletion of tetrahydrobiopterin and neuronal nitric-oxide synthase-derived superoxide. J Biol Chem. 279:19099–19112. 2004. View Article : Google Scholar
13	Hartley A, Stone JM, Heron C, Cooper JM and Schapira AH: Complex I inhibitors induce dose-dependent apoptosis in PC12 cells: relevance to Parkinson’s disease. J Neurochem. 63:1987–1990. 1994.PubMed/NCBI
14	Kreutzberg GW: Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19:312–318. 1996. View Article : Google Scholar : PubMed/NCBI
15	Monahan AJ, Warren M and Carvey PM: Neuroinflammation and peripheral immune infiltration in Parkinson’s disease: an autoimmune hypothesis. Cell Transplant. 17:363–372. 2008.
16	Hirsch EC and Hunot S: Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8:382–397. 2009.
17	Gao HM, Zhou H, Zhang F, Wilson BC, Kam W and Hong JS: HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. J Neurosci. 31:1081–1092. 2011. View Article : Google Scholar : PubMed/NCBI
18	McGeer PL, Schwab C, Parent A and Doudet D: Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann Neurol. 54:599–604. 2003.
19	Block ML, Zecca L and Hong JS: Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 8:57–69. 2007. View Article : Google Scholar : PubMed/NCBI
20	Gao HM, Liu B, Zhang W and Hong JS: Novel anti-inflammatory therapy for Parkinson’s disease. Trends Pharmacol Sci. 24:395–401. 2003.
21	Wu DC, Teismann P, Tieu K, et al: NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Proc Natl Acad Sci USA. 100:6145–6150. 2003.
22	Zhang F, Qian L, Flood PM, Shi JS, Hong JS and Gao HM: Inhibition of IkappaB kinase-beta protects dopamine neurons against lipopolysaccharide-induced neurotoxicity. J Pharmacol Exp Ther. 333:822–833. 2010. View Article : Google Scholar : PubMed/NCBI
23	Wang W, Yang Y, Ying C, et al: Inhibition of glycogen synthase kinase-3beta protects dopaminergic neurons from MPTP toxicity. Neuropharmacology. 52:1678–1684. 2007. View Article : Google Scholar : PubMed/NCBI
24	King TD, Bijur GN and Jope RS: Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium. Brain Res. 919:106–114. 2001. View Article : Google Scholar : PubMed/NCBI
25	Woodgett JR: Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 9:2431–2438. 1990.PubMed/NCBI
26	Parker PJ, Embi N, Caudwell FB and Cohen P: Glycogen synthase from rabbit skeletal muscle. State of phosphorylation of the seven phosphoserine residues in vivo in the presence and absence of adrenaline. Eur J Biochem. 124:47–55. 1982. View Article : Google Scholar : PubMed/NCBI
27	Jope RS and Johnson GV: The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 29:95–102. 2004. View Article : Google Scholar : PubMed/NCBI
28	Kockeritz L, Doble B, Patel S and Woodgett JR: Glycogen synthase kinase-3 - an overview of an over-achieving protein kinase. Curr Drug Targets. 7:1377–1388. 2006. View Article : Google Scholar : PubMed/NCBI
29	Miura T, Tanno M and Sato T: Mitochondrial kinase signalling pathways in myocardial protection from ischaemia/reperfusion-induced necrosis. Cardiovasc Res. 88:7–15. 2010. View Article : Google Scholar : PubMed/NCBI
30	Medina M, Garrido JJ and Wandosell FG: Modulation of GSK-3 as a Therapeutic Strategy on Tau Pathologies. Front Mol Neurosci. 4:242011. View Article : Google Scholar : PubMed/NCBI
31	King MR, Anderson NJ, Guernsey LS and Jolivalt CG: Glycogen synthase kinase-3 inhibition prevents learning deficits in diabetic mice. J Neurosci Res. 91:506–514. 2013. View Article : Google Scholar : PubMed/NCBI
32	Zheng H, Li W, Wang Y, et al: Glycogen synthase kinase-3 beta regulates Snail and beta-catenin expression during Fas-induced epithelial-mesenchymal transition in gastrointestinal cancer. Eur J Cancer. 2013. View Article : Google Scholar
33	Dajani R, Fraser E, Roe SM, et al: Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell. 105:721–732. 2001.PubMed/NCBI
34	Xavier IJ, Mercier PA, McLoughlin CM, Ali A, Woodgett JR and Ovsenek N: Glycogen synthase kinase 3beta negatively regulates both DNA-binding and transcriptional activities of heat shock factor 1. J Biol Chem. 275:29147–29152. 2000. View Article : Google Scholar : PubMed/NCBI
35	Bijur GN and Jope RS: Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem. 276:37436–37442. 2001. View Article : Google Scholar : PubMed/NCBI
36	Bijur GN and Jope RS: Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria. Neuroreport. 14:2415–2419. 2003. View Article : Google Scholar : PubMed/NCBI
37	Hoshi M, Sato M, Kondo S, et al: Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria. J Biochem. 118:683–685. 1995.PubMed/NCBI
38	Senatorov VV, Ren M, Kanai H, Wei H and Chuang DM: Short-term lithium treatment promotes neuronal survival and proliferation in rat striatum infused with quinolinic acid, an excitotoxic model of Huntington’s disease. Mol Psychiatry. 9:371–385. 2004.PubMed/NCBI
39	Bijur GN, De Sarno P and Jope RS: Glycogen synthase kinase-3beta facilitates staurosporine- and heat shock-induced apoptosis. Protection by lithium. J Biol Chem. 275:7583–7590. 2000. View Article : Google Scholar : PubMed/NCBI
40	Alvarez AR, Godoy JA, Mullendorff K, Olivares GH, Bronfman M and Inestrosa NC: Wnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons. Exp Cell Res. 297:186–196. 2004. View Article : Google Scholar : PubMed/NCBI
41	Wu Y, Shang Y, Sun S, Liang H and Liu R: Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/GSK-3beta/caspase-3 mediated signaling pathway. Apoptosis. 12:1365–1375. 2007. View Article : Google Scholar : PubMed/NCBI
42	Petit-Paitel A, Brau F, Cazareth J and Chabry J: Involvment of cytosolic and mitochondrial GSK-3beta in mitochondrial dysfunction and neuronal cell death of MPTP/MPP-treated neurons. PLoS One. 4:e54912009. View Article : Google Scholar : PubMed/NCBI
43	King TD, Clodfelder-Miller B, Barksdale KA and Bijur GN: Unregulated mitochondrial GSK3beta activity results in NADH: ubiquinone oxidoreductase deficiency. Neurotox Res. 14:367–382. 2008. View Article : Google Scholar : PubMed/NCBI
44	Huang WC, Lin YS, Wang CY, et al: Glycogen synthase kinase-3 negatively regulates anti-inflammatory interleukin-10 for lipopolysaccharide-induced iNOS/NO biosynthesis and RANTES production in microglial cells. Immunology. 128:e275–e286. 2009. View Article : Google Scholar : PubMed/NCBI
45	Yuskaitis CJ and Jope RS: Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell Signal. 21:264–273. 2009. View Article : Google Scholar : PubMed/NCBI
46	Camello-Almaraz C, Gomez-Pinilla PJ, Pozo MJ and Camello PJ: Mitochondrial reactive oxygen species and Ca²⁺signaling. Am J Physiol Cell Physiol. 291:C1082–C1088. 2006. View Article : Google Scholar : PubMed/NCBI
47	Grivennikova VG and Vinogradov AD: Generation of superoxide by the mitochondrial Complex I. Biochim Biophys Acta. 1757:553–561. 2006. View Article : Google Scholar : PubMed/NCBI
48	Abou-Sleiman PM, Muqit MM and Wood NW: Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci. 7:207–219. 2006.
49	Langston JW, Ballard P, Tetrud JW and Irwin I: Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 219:979–980. 1983. View Article : Google Scholar : PubMed/NCBI
50	Chiba K, Trevor A and Castagnoli N Jr: Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun. 120:574–578. 1984. View Article : Google Scholar : PubMed/NCBI
51	Javitch JA, D’Amato RJ, Strittmatter SM and Snyder SH: Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA. 82:2173–2177. 1985. View Article : Google Scholar
52	Bindoff LA, Birch-Machin M, Cartlidge NE, Parker WD Jr and Turnbull DM: Mitochondrial function in Parkinson’s disease. Lancet. 2:491989.
53	Kussmaul L and Hirst J: The mechanism of superoxide production by NADH: ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc Natl Acad Sci USA. 103:7607–7612. 2006. View Article : Google Scholar : PubMed/NCBI
54	Sipos I, Tretter L and Adam-Vizi V: Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals. J Neurochem. 84:112–118. 2003. View Article : Google Scholar : PubMed/NCBI
55	Murphy MP: How mitochondria produce reactive oxygen species. Biochem J. 417:1–13. 2009. View Article : Google Scholar : PubMed/NCBI
56	Cassarino DS, Fall CP, Swerdlow RH, et al: Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson’s disease. Biochim Biophys Acta. 1362:77–86. 1997.PubMed/NCBI
57	Pastorino JG, Hoek JB and Shulga N: Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res. 65:10545–10554. 2005. View Article : Google Scholar
58	Watcharasit P, Bijur GN, Song L, Zhu J, Chen X and Jope RS: Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. J Biol Chem. 278:48872–48879. 2003. View Article : Google Scholar : PubMed/NCBI
59	Valerio A, Bertolotti P, Delbarba A, et al: Glycogen synthase kinase-3 inhibition reduces ischemic cerebral damage, restores impaired mitochondrial biogenesis and prevents ROS production. J Neurochem. 116:1148–1159. 2011. View Article : Google Scholar
60	Vila M and Przedborski S: Targeting programmed cell death in neurodegenerative diseases. Nat Rev Neurosci. 4:365–375. 2003. View Article : Google Scholar : PubMed/NCBI
61	Perier C, Tieu K, Guegan C, et al: Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage. Proc Natl Acad Sci USA. 102:19126–19131. 2005. View Article : Google Scholar : PubMed/NCBI
62	Roucou X and Martinou JC: Conformational change of Bax: a question of life or death. Cell Death Differ. 8:875–877. 2001. View Article : Google Scholar : PubMed/NCBI
63	Obame FN, Plin-Mercier C, Assaly R, et al: Cardioprotective effect of morphine and a blocker of glycogen synthase kinase 3 beta, SB216763 [3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], via inhibition of the mitochondrial permeability transition pore. J Pharmacol Exp Ther. 326:252–258. 2008.PubMed/NCBI
64	Nishihara M, Miura T, Miki T, et al: Modulation of the mitochondrial permeability transition pore complex in GSK-3beta-mediated myocardial protection. J Mol Cell Cardiol. 43:564–570. 2007. View Article : Google Scholar : PubMed/NCBI
65	Feng J, Lucchinetti E, Ahuja P, Pasch T, Perriard JC and Zaugg M: Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta. Anesthesiology. 103:987–995. 2005. View Article : Google Scholar
66	Park SS, Zhao H, Mueller RA and Xu Z: Bradykinin prevents reperfusion injury by targeting mitochondrial permeability transition pore through glycogen synthase kinase 3beta. J Mol Cell Cardiol. 40:708–716. 2006. View Article : Google Scholar : PubMed/NCBI
67	Gomez L, Paillard M, Thibault H, Derumeaux G and Ovize M: Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion. Circulation. 117:2761–2768. 2008. View Article : Google Scholar : PubMed/NCBI
68	Zhou K, Zhang L, Xi J, Tian W and Xu Z: Ethanol prevents oxidant-induced mitochondrial permeability transition pore opening in cardiac cells. Alcohol Alcohol. 44:20–24. 2009. View Article : Google Scholar : PubMed/NCBI
69	Youdim MB and Arraf Z: Prevention of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) dopaminergic neurotoxicity in mice by chronic lithium: involvements of Bcl-2 and Bax. Neuropharmacology. 46:1130–1140. 2004. View Article : Google Scholar : PubMed/NCBI
70	Linseman DA, Butts BD, Precht TA, et al: Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci. 24:9993–10002. 2004. View Article : Google Scholar : PubMed/NCBI
71	Maurer U, Charvet C, Wagman AS, Dejardin E and Green DR: Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 21:749–760. 2006. View Article : Google Scholar : PubMed/NCBI
72	Tsujimoto Y and Shimizu S: VDAC regulation by the Bcl-2 family of proteins. Cell Death Differ. 7:1174–1181. 2000. View Article : Google Scholar : PubMed/NCBI
73	Martinou JC and Green DR: Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol. 2:63–67. 2001. View Article : Google Scholar : PubMed/NCBI
74	Armstrong JS: Mitochondrial membrane permeabilization: the sine qua non for cell death. Bioessays. 28:253–260. 2006. View Article : Google Scholar : PubMed/NCBI
75	Gollapudi S, McCormick MJ and Gupta S: Changes in mitochondrial membrane potential and mitochondrial mass occur independent of the activation of caspase-8 and caspase-3 during CD95-mediated apoptosis in peripheral blood T cells. Int J Oncol. 22:597–600. 2003.PubMed/NCBI
76	Tan J, Zhuang L, Leong HS, Iyer NG, Liu ET and Yu Q: Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cells. Cancer Res. 65:9012–9020. 2005. View Article : Google Scholar
77	Chen G, Zeng WZ, Yuan PX, et al: The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS. J Neurochem. 72:879–882. 1999. View Article : Google Scholar : PubMed/NCBI
78	Kaga S, Zhan L, Altaf E and Maulik N: Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium. J Mol Cell Cardiol. 40:138–147. 2006. View Article : Google Scholar
79	Chen RW and Chuang DM: Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem. 274:6039–6042. 1999. View Article : Google Scholar : PubMed/NCBI
80	Ohori K, Miura T, Tanno M, et al: Ser9 phosphorylation of mitochondrial GSK-3beta is a primary mechanism of cardiomyocyte protection by erythropoietin against oxidant-induced apoptosis. Am J Physiol Heart Circ Physiol. 295:H2079–H2086. 2008. View Article : Google Scholar : PubMed/NCBI
81	Ge XH, Zhu GJ, Geng DQ, Zhang ZJ and Liu CF: Erythropoietin attenuates 6-hydroxydopamine-induced apoptosis via glycogen synthase kinase 3b-mediated mitochondrial translocation of Bax in PC12 cells. Neurol Sci. 33:1249–1256. 2012. View Article : Google Scholar
82	Ngok-Ngam P, Watcharasit P, Thiantanawat A and Satayavivad J: Pharmacological inhibition of GSK3 attenuates DNA damage-induced apoptosis via reduction of p53 mitochondrial translocation and Bax oligomerization in neuroblastoma SH-SY5Y cells. Cell Mol Biol Lett. 18:58–74. 2013. View Article : Google Scholar : PubMed/NCBI
83	Samii A, Nutt JG and Ransom BR: Parkinson’s disease. Lancet. 363:1783–1793. 2004.
84	Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R and Goedert M: Alpha-synuclein in Lewy bodies. Nature. 388:839–840. 1997. View Article : Google Scholar : PubMed/NCBI
85	Singleton AB, Farrer M, Johnson J, et al: alpha-Synuclein locus triplication causes Parkinson’s disease. Science. 302:8412003.
86	Liu D, Jin L, Wang H, et al: Silencing alpha-synuclein gene expression enhances tyrosine hydroxylase activity in MN9D cells. Neurochem Res. 33:1401–1409. 2008. View Article : Google Scholar : PubMed/NCBI
87	Baptista MJ, O’Farrell C, Daya S, et al: Co-ordinate transcriptional regulation of dopamine synthesis genes by alpha-synuclein in human neuroblastoma cell lines. J Neurochem. 85:957–968. 2003. View Article : Google Scholar : PubMed/NCBI
88	Perez RG, Waymire JC, Lin E, Liu JJ, Guo F and Zigmond MJ: A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci. 22:3090–3099. 2002.
89	Yu S, Zuo X, Li Y, et al: Inhibition of tyrosine hydroxylase expression in alpha-synuclein-transfected dopaminergic neuronal cells. Neurosci Lett. 367:34–39. 2004. View Article : Google Scholar : PubMed/NCBI
90	Danzer KM, Haasen D, Karow AR, et al: Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci. 27:9220–9232. 2007. View Article : Google Scholar : PubMed/NCBI
91	Periquet M, Fulga T, Myllykangas L, Schlossmacher MG and Feany MB: Aggregated alpha-synuclein mediates dopaminergic neurotoxicity in vivo. J Neurosci. 27:3338–3346. 2007. View Article : Google Scholar : PubMed/NCBI
92	Desplats P, Lee HJ, Bae EJ, et al: Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA. 106:13010–13015. 2009. View Article : Google Scholar : PubMed/NCBI
93	Masliah E, Rockenstein E, Veinbergs I, et al: Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science. 287:1265–1269. 2000. View Article : Google Scholar : PubMed/NCBI
94	Parihar MS, Parihar A, Fujita M, Hashimoto M and Ghafourifar P: Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci. 65:1272–1284. 2008. View Article : Google Scholar : PubMed/NCBI
95	Parihar MS, Parihar A, Fujita M, Hashimoto M and Ghafourifar P: Alpha-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells. Int J Biochem Cell Biol. 41:2015–2024. 2009. View Article : Google Scholar
96	Hsu LJ, Sagara Y, Arroyo A, et al: alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol. 157:401–410. 2000. View Article : Google Scholar : PubMed/NCBI
97	Feng LR, Federoff HJ, Vicini S and Maguire-Zeiss KA: Alpha-synuclein mediates alterations in membrane conductance: a potential role for alpha-synuclein oligomers in cell vulnerability. Eur J Neurosci. 32:10–17. 2010. View Article : Google Scholar : PubMed/NCBI
98	Lee EJ, Woo MS, Moon PG, et al: Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J Immunol. 185:615–623. 2010. View Article : Google Scholar : PubMed/NCBI
99	Su X, Federoff HJ and Maguire-Zeiss KA: Mutant alpha-synuclein overexpression mediates early proinflammatory activity. Neurotox Res. 16:238–254. 2009. View Article : Google Scholar : PubMed/NCBI
100	Theodore S, Cao S, McLean PJ and Standaert DG: Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol. 67:1149–1158. 2008. View Article : Google Scholar
101	Kozikowski AP, Gaisina IN, Petukhov PA, et al: Highly potent and specific GSK-3beta inhibitors that block tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson’s disease. ChemMedChem. 1:256–266. 2006.PubMed/NCBI
102	Haggerty T, Credle J, Rodriguez O, et al: Hyperphosphorylated Tau in an alpha-synuclein-overexpressing transgenic model of Parkinson’s disease. Eur J Neurosci. 33:1598–1610. 2011.PubMed/NCBI
103	Wills J, Jones J, Haggerty T, Duka V, Joyce JN and Sidhu A: Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson’s disease brains with and without dementia. Exp Neurol. 225:210–218. 2010.
104	Cho JH and Johnson GV: Glycogen synthase kinase 3 beta induces caspase-cleaved tau aggregation in situ. J Biol Chem. 279:54716–54723. 2004. View Article : Google Scholar : PubMed/NCBI
105	Peng JH, Zhang CE, Wei W, Hong XP, Pan XP and Wang JZ: Dehydroevodiamine attenuates tau hyperphosphorylation and spatial memory deficit induced by activation of glycogen synthase kinase-3 in rats. Neuropharmacology. 52:1521–1527. 2007. View Article : Google Scholar : PubMed/NCBI
106	Chun W and Johnson GV: Activation of glycogen synthase kinase 3beta promotes the intermolecular association of tau. The use of fluorescence resonance energy transfer microscopy. J Biol Chem. 282:23410–23417. 2007. View Article : Google Scholar : PubMed/NCBI
107	Greco SJ, Sarkar S, Casadesus G, et al: Leptin inhibits glycogen synthase kinase-3beta to prevent tau phosphorylation in neuronal cells. Neurosci Lett. 455:191–194. 2009. View Article : Google Scholar : PubMed/NCBI
108	Crouch PJ, Hung LW, Adlard PA, et al: Increasing Cu bioavailability inhibits Abeta oligomers and tau phosphorylation. Proc Natl Acad Sci USA. 106:381–386. 2009. View Article : Google Scholar : PubMed/NCBI
109	Engel T, Lucas JJ, Gomez-Ramos P, Moran MA, Avila J and Hernandez F: Cooexpression of FTDP-17 tau and GSK-3beta in transgenic mice induce tau polymerization and neurodegeneration. Neurobiol Aging. 27:1258–1268. 2006. View Article : Google Scholar : PubMed/NCBI
110	Engel T, Hernandez F, Avila J and Lucas JJ: Full reversal of Alzheimer’s disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3. J Neurosci. 26:5083–5090. 2006.
111	Perez M, Hernandez F, Lim F, Diaz-Nido J and Avila J: Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J Alzheimers Dis. 5:301–308. 2003.PubMed/NCBI
112	Nakashima H, Ishihara T, Suguimoto P, et al: Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol. 110:547–556. 2005. View Article : Google Scholar : PubMed/NCBI
113	Engel T, Goni-Oliver P, Lucas JJ, Avila J and Hernandez F: Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J Neurochem. 99:1445–1455. 2006. View Article : Google Scholar : PubMed/NCBI
114	Gao HM and Hong JS: Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol. 29:357–365. 2008. View Article : Google Scholar : PubMed/NCBI
115	Kim SU and de Vellis J: Microglia in health and disease. J Neurosci Res. 81:302–313. 2005. View Article : Google Scholar : PubMed/NCBI
116	Mrak RE and Griffin WS: Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging. 26:349–354. 2005. View Article : Google Scholar : PubMed/NCBI
117	McGeer PL and McGeer EG: Glial reactions in Parkinson’s disease. Mov Disord. 23:474–483. 2008.
118	Ouchi Y, Yagi S, Yokokura M and Sakamoto M: Neuroinflammation in the living brain of Parkinson’s disease. Parkinsonism Relat Disord. 15 Suppl 3:S200–S204. 2009.
119	Hunot S, Dugas N, Faucheux B, et al: FcepsilonRII/CD23 is expressed in Parkinson’s disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells. J Neurosci. 19:3440–3447. 1999.PubMed/NCBI
120	Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M and Nagatsu T: Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci Lett. 211:13–16. 1996.PubMed/NCBI
121	Koziorowski D, Tomasiuk R, Szlufik S and Friedman A: Inflammatory cytokines and NT-proCNP in Parkinson’s disease patients. Cytokine. 60:762–766. 2012.
122	Przedborski S: Inflammation and Parkinson’s disease pathogenesis. Mov Disord. 25 Suppl 1:S55–S57. 2010.
123	Frankola KA, Greig NH, Luo W and Tweedie D: Targeting TNF-alpha to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS Neurol Disord Drug Targets. 10:391–403. 2011. View Article : Google Scholar : PubMed/NCBI
124	Qian L, Flood PM and Hong JS: Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J Neural Transm. 117:971–979. 2010.
125	Lofrumento DD, Nicolardi G, Cianciulli A, et al: Neuroprotective effects of resveratrol in an MPTP mouse model of Parkinson’s-like disease: Possible role of SOCS-1 in reducing pro-inflammatory responses. Innate Immun. 2013.PubMed/NCBI
126	Martin M, Rehani K, Jope RS and Michalek SM: Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol. 6:777–784. 2005. View Article : Google Scholar : PubMed/NCBI
127	Jope RS, Yuskaitis CJ and Beurel E: Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res. 32:577–595. 2007. View Article : Google Scholar : PubMed/NCBI
128	Beurel E and Jope RS: Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain. J Neuroinflammation. 6:92009. View Article : Google Scholar : PubMed/NCBI
129	Cheng YL, Wang CY, Huang WC, et al: Staphylococcus aureus induces microglial inflammation via a glycogen synthase kinase 3beta-regulated pathway. Infect Immun. 77:4002–4008. 2009. View Article : Google Scholar : PubMed/NCBI
130	Wang MJ, Huang HY, Chen WF, Chang HF and Kuo JS: Glycogen synthase kinase-3beta inactivation inhibits tumor necrosis factor-alpha production in microglia by modulating nuclear factor kappaB and MLK3/JNK signaling cascades. J Neuroinflammation. 7:992010. View Article : Google Scholar
131	Colasanti M, Persichini T, Di Pucchio T, Gremo F and Lauro GM: Human ramified microglial cells produce nitric oxide upon Escherichia coli lipopolysaccharide and tumor necrosis factor alpha stimulation. Neurosci Lett. 200:144–146. 1995. View Article : Google Scholar
132	Block ML and Hong JS: Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochem Soc Trans. 35:1127–1132. 2007. View Article : Google Scholar : PubMed/NCBI
133	Członkowska A, Kohutnicka M, Kurkowska-Jastrzebska I and Członkowski A: Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s disease mice model. Neurodegeneration. 5:137–143. 1996.
134	Przedborski S and Vila M: The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson’s disease. Ann NY Acad Sci. 991:189–198. 2003.PubMed/NCBI
135	Duka T, Duka V, Joyce JN and Sidhu A: Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson’s disease models. FASEB J. 23:2820–2830. 2009.PubMed/NCBI
136	Watcharasit P, Thiantanawat A and Satayavivad J: GSK3 promotes arsenite-induced apoptosis via facilitation of mitochondria disruption. J Appl Toxicol. 28:466–474. 2008. View Article : Google Scholar : PubMed/NCBI
137	Cookson MR: The biochemistry of Parkinson’s disease. Annu Rev Biochem. 74:29–52. 2005.