Mitochondrial neuronal uncoupling proteins: a target for potential disease-modification in Parkinson's disease

Translational Neurodegeneration

Shu-Leong Ho³  David B Ramsden²  Koon-Ho Chan³  Zero HM Tse¹  Danny HF So¹  Hui-Fang Liu¹  Jessica WM Ho¹  Philip WL Ho³ 

[1] Division of Neurology, Department of Medicine, University of Hong Kong, Pokfulam, Hong Kong SAR, China;School of Medicine and School of Biosciences, University of Birmingham, Birmingham, UK;Research Centre of Heart, Brain, Hormone and Healthy Aging (HBHA), University of Hong Kong, Pokfulam, Hong Kong SAR, China

关键词: neuroprotection;    oxidative stress;    ATP;    Parkinson's disease;    mitochondria;    uncoupling proteins;   

Others  :  839042
DOI  :  10.1186/2047-9158-1-3

 received in 2011-12-08, accepted in 2012-01-13,  发布年份 2012

【 摘 要 】

This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinson's disease (PD). Mitochondria provide cellular energy in the form of ATP via oxidative phosphorylation, but as an integral part of this process, superoxides and other reactive oxygen species are also produced. Excessive free radical production contributes to oxidative stress. Cells have evolved to handle such stress via various endogenous anti-oxidant proteins. One such family of proteins is the mitochondrial uncoupling proteins (UCPs), which are anion carriers located in the mitochondrial inner membrane. There are five known homologues (UCP1 to 5), of which UCP4 and 5 are predominantly expressed in neural cells. In a series of previous publications, we have shown how these neuronal UCPs respond to 1-methyl-4-phenylpyridinium (MPP⁺; toxic metabolite of MPTP) and dopamine-induced toxicity to alleviate neuronal cell death by preserving ATP levels and mitochondrial membrane potential, and reducing oxidative stress. We also showed how their expression can be influenced by nuclear factor kappa-B (NF-κB) signaling pathway specifically in UCP4. Furthermore, we previously reported an interesting link between PD and metabolic processes through the protective effects of leptin (hormone produced by adipocytes) acting via UCP2 against MPP⁺-induced toxicity. There is increasing evidence that these endogenous neuronal UCPs can play a vital role to protect neurons against various pathogenic stresses including those associated with PD. Their expression, which can be induced, may well be a potential therapeutic target for various drugs to alleviate the harmful effects of pathogenic processes in PD and hence modify the progression of this disease.

【 授权许可】

   
2012 Ho et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Schapira AH, Jenner P: Etiology and pathogenesis of Parkinson's disease. Mov Disord 2011, 26:1049-1055.
• [2]Schapira AH: Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol 2008, 7:97-109.
• [3]Bueler H: Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. Exp Neurol 2009, 218:235-246.
• [4]Tansey MG, McCoy MK, Frank-Cannon TC: Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 2007, 208:1-25.
• [5]Parker WD Jr, Boyson SJ, Parks JK: Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol 1989, 26:719-723.
• [6]Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983, 219:979-980.
• [7]Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT: Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 2000, 3:1301-1306.
• [8]Swerdlow RH, Parks JK, Miller SW, Tuttle JB, Trimmer PA, Sheehan JP, Bennett JP Jr, Davis RE, Parker WD Jr: Origin and functional consequences of the complex I defect in Parkinson's disease. Ann Neurol 1996, 40:663-671.
• [9]Trimmer PA, Swerdlow RH, Parks JK, Keeney P, Bennett JP Jr, Miller SW, Davis RE, Parker WD Jr: Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines. Exp Neurol 2000, 162:37-50.
• [10]Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, et al.: Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 2004, 429:417-423.
• [11]Sian J, Dexter DT, Lees AJ, Daniel S, Jenner P, Marsden CD: Glutathione-related enzymes in brain in Parkinson's disease. Ann Neurol 1994, 36:356-361.
• [12]Owen AD, Schapira AH, Jenner P, Marsden CD: Oxidative stress and Parkinson's disease. Ann N Y Acad Sci 1996, 786:217-223.
• [13]Karp G: Bioenergetics, Enzymes, and Metabolism. In Cell and molecular biology: concepts and experiments. 5th edition. Chichester: John Wiley & Sons; 2008:85-119.
• [14]Mitchell P: Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 1961, 191:144-148.
• [15]Hatefi Y, Hanstein WG, Galante Y, Stiggall DL: Mitochondrial ATP-Pi exchange complex and the site of uncoupling of oxidative phosphorylation. Fed Proc 1975, 34:1699-1706.
• [16]Ricquier D, Bouillaud F: The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J 2000, 345 Pt 2:161-179.
• [17]Porter RK: Mitochondrial proton leak: a role for uncoupling proteins 2 and 3? Biochim Biophys Acta 2001, 1504:120-127.
• [18]Cannon B, Shabalina IG, Kramarova TV, Petrovic N, Nedergaard J: Uncoupling proteins: a role in protection against reactive oxygen species--or not? Biochim Biophys Acta 2006, 1757:449-458.
• [19]Skulachev VP: Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta 1998, 1363:100-124.
• [20]Echtay KS, Brand MD: 4-hydroxy-2-nonenal and uncoupling proteins: an approach for regulation of mitochondrial ROS production. Redox Rep 2007, 12:26-29.
• [21]Nicholls DG, Bernson VS, Heaton GM: The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation. Experientia Suppl 1978, 32:89-93.
• [22]Stuart JA, Harper JA, Brindle KM, Jekabsons MB, Brand MD: A mitochondrial uncoupling artifact can be caused by expression of uncoupling protein 1 in yeast. Biochem J 2001, 356:779-789.
• [23]Fleury C, Neverova M, Collins S, Raimbault S, Champigny O, Levi-Meyrueis C, Bouillaud F, Seldin MF, Surwit RS, Ricquier D, Warden CH: Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997, 15:269-272.
• [24]Boss O, Samec S, Paoloni-Giacobino A, Rossier C, Dulloo A, Seydoux J, Muzzin P, Giacobino JP: Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett 1997, 408:39-42.
• [25]Mao W, Yu XX, Zhong A, Li W, Brush J, Sherwood SW, Adams SH, Pan G: UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett 1999, 443:326-330.
• [26]Sanchis D, Fleury C, Chomiki N, Goubern M, Huang Q, Neverova M, Gregoire F, Easlick J, Raimbault S, Levi-Meyrueis C, et al.: BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast. J Biol Chem 1998, 273:34611-34615.
• [27]Kim-Han JS, Reichert SA, Quick KL, Dugan LL: BMCP1: a mitochondrial uncoupling protein in neurons which regulates mitochondrial function and oxidant production. J Neurochem 2001, 79:658-668.
• [28]Yu XX, Mao W, Zhong A, Schow P, Brush J, Sherwood SW, Adams SH, Pan G: Characterization of novel UCP5/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation. Faseb J 2000, 14:1611-1618.
• [29]Alan L, Smolkova K, Kronusova E, Santorova J, Jezek P: Absolute levels of transcripts for mitochondrial uncoupling proteins UCP2, UCP3, UCP4, and UCP5 show different patterns in rat and mice tissues. J Bioenerg Biomembr 2009, 41:71-78.
• [30]Miroux B, Frossard V, Raimbault S, Ricquier D, Bouillaud F: The topology of the brown adipose tissue mitochondrial uncoupling protein determined with antibodies against its antigenic sites revealed by a library of fusion proteins. EMBO J 1993, 12:3739-3745.
• [31]Jezek P, Jezek J: Sequence anatomy of mitochondrial anion carriers. FEBS Lett 2003, 534:15-25.
• [32]Ho PW, Chan DY, Kwok KH, Chu AC, Ho JW, Kung MH, Ramsden DB, Ho SL: Methyl-4-phenylpyridinium ion modulates expression of mitochondrial uncoupling proteins 2, 4, and 5 in catecholaminergic (SK-N-SH) cells. J Neurosci Res 2005, 81:261-268.
• [33]Nakase T, Yoshida Y, Nagata K: Amplified expression of uncoupling proteins in human brain ischemic lesions. Neuropathology 2007, 27:442-447.
• [34]Xu R, Wu C, Zhang X, Zhang Q, Yang Y, Yi J, Yang R, Tao Y: Linking hypoxic and oxidative insults to cell death mechanisms in models of ALS. Brain Res 2011, 1372:133-144.
• [35]Santandreu FM, Valle A, Fernandez de Mattos S, Roca P, Oliver J: Hydrogen peroxide regulates the mitochondrial content of uncoupling protein 5 in colon cancer cells. Cell Physiol Biochem 2009, 24:379-390.
• [36]Chu AC, Ho PW, Kwok KH, Ho JW, Chan KH, Liu HF, Kung MH, Ramsden DB, Ho SL: Mitochondrial UCP4 attenuates MPP+ - and dopamine-induced oxidative stress, mitochondrial depolarization, and ATP deficiency in neurons and is interlinked with UCP2 expression. Free Radic Biol Med 2009, 46:810-820.
• [37]Kwok KH, Ho PW, Chu AC, Ho JW, Liu HF, Yiu DC, Chan KH, Kung MH, Ramsden DB, Ho SL: Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity. Free Radic Biol Med 2010, 49:1023-1035.
• [38]Keller PA, Lehr L, Giacobino JP, Charnay Y, Assimacopoulos-Jeannet F, Giovannini N: Cloning, ontogenesis, and localization of an atypical uncoupling protein 4 in Xenopus laevis. Physiol Genomics 2005, 22:339-345.
• [39]Fuxe K, Rivera A, Jacobsen KX, Hoistad M, Leo G, Horvath TL, Staines W, De la Calle A, Agnati LF: Dynamics of volume transmission in the brain. Focus on catecholamine and opioid peptide communication and the role of uncoupling protein 2. J Neural Transm 2005, 112:65-76.
• [40]Horvath TL, Warden CH, Hajos M, Lombardi A, Goglia F, Diano S: Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J Neurosci 1999, 19:10417-10427.
• [41]Lengacher S, Magistretti PJ, Pellerin L: Quantitative rt-PCR analysis of uncoupling protein isoforms in mouse brain cortex: methodological optimization and comparison of expression with brown adipose tissue and skeletal muscle. J Cereb Blood Flow Metab 2004, 24:780-788.
• [42]Andrews ZB, Horvath B, Barnstable CJ, Elsworth J, Yang L, Beal MF, Roth RH, Matthews RT, Horvath TL: Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. J Neurosci 2005, 25:184-191.
• [43]Jaburek M, Miyamoto S, Di Mascio P, Garlid KD, Jezek P: Hydroperoxy fatty acid cycling mediated by mitochondrial uncoupling protein UCP2. J Biol Chem 2004, 279:53097-53102.
• [44]Echtay KS, Pakay JL, Esteves TC, Brand MD: Hydroxynonenal and uncoupling proteins: a model for protection against oxidative damage. Biofactors 2005, 24:119-130.
• [45]Ho PW, Chu AC, Kwok KH, Kung MH, Ramsden DB, Ho SL: Knockdown of uncoupling protein-5 in neuronal SH-SY5Y cells: Effects on MPP+-induced mitochondrial membrane depolarization, ATP deficiency, and oxidative cytotoxicity. J Neurosci Res 2006, 84:1358-1366.
• [46]Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP: The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 2009, 11:747-752.
• [47]Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD: Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem 1990, 54:823-827.
• [48]Waldeck-Weiermair M, Jean-Quartier C, Rost R, Khan MJ, Vishnu N, Bondarenko AI, Imamura H, Malli R, Graier WF: Leucine Zipper EF Hand-containing Transmembrane Protein 1 (Letm1) and Uncoupling Proteins 2 and 3 (UCP2/3) Contribute to Two Distinct Mitochondrial Ca2+ Uptake Pathways. J Biol Chem 2011, 286:28444-28455.
• [49]Ho PW, Liu HF, Ho JW, Zhang WY, Chu AC, Kwok KH, Ge X, Chan KH, Ramsden DB, Ho SL: Mitochondrial uncoupling protein-2 (UCP2) mediates leptin protection against MPP+ toxicity in neuronal cells. Neurotox Res 2010, 17:332-343.
• [50]Shang Y, Liu Y, Du L, Wang Y, Cheng X, Xiao W, Wang X, Jin H, Yang X, Liu S, Chen Q: Targeted expression of uncoupling protein 2 to mouse liver increases the susceptibility to lipopolysaccharide/galactosamine-induced acute liver injury. Hepatology 2009, 50:1204-1216.
• [51]Diano S, Matthews RT, Patrylo P, Yang L, Beal MF, Barnstable CJ, Horvath TL: Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology 2003, 144:5014-5021.
• [52]Pfeiffer M, Kayser EB, Yang X, Abramson E, Kenaston MA, Lago CU, Lo HH, Sedensky MM, Lunceford A, Clarke CF, et al.: Caenorhabditis elegans UCP4 controls complex II-mediated oxidative phosphorylation through succinate transport. J Biol Chem 2011.
• [53]Liu D, Chan SL, de Souza-Pinto NC, Slevin JR, Wersto RP, Zhan M, Mustafa K, de Cabo R, Mattson MP: Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. Neuromolecular Med 2006, 8:389-414.
• [54]Hanak P, Jezek P: Mitochondrial uncoupling proteins and phylogenesis--UCP4 as the ancestral uncoupling protein. FEBS Lett 2001, 495:137-141.
• [55]Ivanova MV, Hoang T, McSorley FR, Krnac G, Smith MD, Jelokhani-Niaraki M: A comparative study on conformation and ligand binding of the neuronal uncoupling proteins. Biochemistry 2010, 49:512-521.
• [56]Surmeier DJ, Guzman JN, Sanchez-Padilla J: Calcium, cellular aging, and selective neuronal vulnerability in Parkinson's disease. Cell Calcium 2010, 47:175-182.
• [57]Trenker M, Malli R, Fertschai I, Levak-Frank S, Graier WF: Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport. Nat Cell Biol 2007, 9:445-452.
• [58]Chan SL, Liu D, Kyriazis GA, Bagsiyao P, Ouyang X, Mattson MP: Mitochondrial uncoupling protein-4 regulates calcium homeostasis and sensitivity to store depletion-induced apoptosis in neural cells. J Biol Chem 2006, 281:37391-37403.
• [59]Wu Z, Zhang J, Zhao B: Superoxide anion regulates the mitochondrial free Ca2+ through uncoupling proteins. Antioxid Redox Signal 2009.
• [60]Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ: Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 2010, 468:696-700.
• [61]Sohal RS, Weindruch R: Oxidative stress, caloric restriction, and aging. Science 1996, 273:59-63.
• [62]Wanagat J, Allison DB, Weindruch R: Caloric intake and aging: mechanisms in rodents and a study in nonhuman primates. Toxicol Sci 1999, 52:35-40.
• [63]Mattison JA, Lane MA, Roth GS, Ingram DK: Calorie restriction in rhesus monkeys. Exp Gerontol 2003, 38:35-46.
• [64]Maswood N, Young J, Tilmont E, Zhang Z, Gash DM, Gerhardt GA, Grondin R, Roth GS, Mattison J, Lane MA, et al.: Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease. Proc Natl Acad Sci USA 2004, 101:18171-18176.
• [65]Casanueva FF, Dieguez C: Neuroendocrine regulation and actions of leptin. Front Neuroendocrinol 1999, 20:317-363.
• [66]Gautron L, Elmquist JK: Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 2011, 121:2087-2093.
• [67]Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS: Role of leptin in the neuroendocrine response to fasting. Nature 1996, 382:250-252.
• [68]Takeda S, Elefteriou F, Karsenty G: Common endocrine control of body weight, reproduction, and bone mass. Annu Rev Nutr 2003, 23:403-411.
• [69]Cohen MM Jr: Role of leptin in regulating appetite, neuroendocrine function, and bone remodeling. Am J Med Genet A 2006, 140:515-524.
• [70]Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM: Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci USA 1997, 94:1023-1028.
• [71]Bates SH, Kulkarni RN, Seifert M, Myers MG Jr: Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis. Cell Metab 2005, 1:169-178.
• [72]Couce ME, Burguera B, Parisi JE, Jensen MD, Lloyd RV: Localization of leptin receptor in the human brain. Neuroendocrinology 1997, 66:145-150.
• [73]Russo VC, Metaxas S, Kobayashi K, Harris M, Werther GA: Antiapoptotic effects of leptin in human neuroblastoma cells. Endocrinology 2004, 145:4103-4112.
• [74]Dzamko NL, Steinberg GR: AMPK-dependent hormonal regulation of whole-body energy metabolism. Acta Physiol (Oxf) 2009, 196:115-127.
• [75]Tu N, Chen H, Winnikes U, Reinert I, Marmann G, Pirke KM, Lentes KU: Molecular cloning and functional characterization of the promoter region of the human uncoupling protein-2 gene. Biochem Biophys Res Commun 1999, 265:326-334.
• [76]Yamada S, Isojima Y, Yamatodani A, Nagai K: Uncoupling protein 2 influences dopamine secretion in PC12h cells. J Neurochem 2003, 87:461-469.
• [77]Esler M, Vaz M, Collier G, Nestel P, Jennings G, Kaye D, Seals D, Lambert G: Leptin in human plasma is derived in part from the brain, and cleared by the kidneys. Lancet 1998, 351:879.
• [78]Opland DM, Leinninger GM, Myers MG Jr: Modulation of the mesolimbic dopamine system by leptin. Brain Res 2010, 1350:65-70.
• [79]Melia HP, Andrews JF, McBennett SM, Porter RK: Effects of acute leptin administration on the differences in proton leak rate in liver mitochondria from ob/ob mice compared to lean controls. FEBS Lett 1999, 458:261-264.
• [80]Meffert MK, Baltimore D: Physiological functions for brain NF-kappaB. Trends Neurosci 2005, 28:37-43.
• [81]Hayden MS, Ghosh S: Shared principles in NF-kappaB signaling. Cell 2008, 132:344-362.
• [82]Hayden MS, West AP, Ghosh S: NF-kappaB and the immune response. Oncogene 2006, 25:6758-6780.
• [83]Karin M, Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005, 5:749-759.
• [84]Kaltschmidt B, Heinrich M, Kaltschmidt C: Stimulus-dependent activation of NF-kappaB specifies apoptosis or neuroprotection in cerebellar granule cells. Neuromolecular Med 2002, 2:299-309.
• [85]Lezoualc'h F, Behl C: Transcription factor NF-kappaB: friend or foe of neurons? Mol Psychiatry 1998, 3:15-20.
• [86]Youdim MB, Grunblatt E, Mandel S: The pivotal role of iron in NF-kappa B activation and nigrostriatal dopaminergic neurodegeneration. Prospects for neuroprotection in Parkinson's disease with iron chelators. Ann N Y Acad Sci 1999, 890:7-25.
• [87]Sarnico I, Boroni F, Benarese M, Sigala S, Lanzillotta A, Battistin L, Spano P, Pizzi M: Activation of NF-kappaB p65/c-Rel dimer is associated with neuroprotection elicited by mGlu5 receptor agonists against MPP(+) toxicity in SK-N-SH cells. J Neural Transm 2008, 115:669-676.
• [88]Aoki E, Yano R, Yokoyama H, Kato H, Araki T: Role of nuclear transcription factor kappa B (NF-kappaB) for MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine)-induced apoptosis in nigral neurons of mice. Exp Mol Pathol 2009, 86:57-64.
• [89]Ghosh A, Roy A, Liu X, Kordower JH, Mufson EJ, Hartley DM, Ghosh S, Mosley RL, Gendelman HE, Pahan K: Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci USA 2007, 104:18754-18759.
• [90]Sarnico I, Lanzillotta A, Boroni F, Benarese M, Alghisi M, Schwaninger M, Inta I, Battistin L, Spano P, Pizzi M: NF-kappaB p50/RelA and c-Rel-containing dimers: opposite regulators of neuron vulnerability to ischaemia. J Neurochem 2009, 108:475-485.
• [91]Pizzi M, Sarnico I, Boroni F, Benarese M, Steimberg N, Mazzoleni G, Dietz GP, Bahr M, Liou HC, Spano PF: NF-kappaB factor c-Rel mediates neuroprotection elicited by mGlu5 receptor agonists against amyloid beta-peptide toxicity. Cell Death Differ 2005, 12:761-772.
• [92]Ho JW, Ho PW, Zhang WY, Liu HF, Kwok KH, Yiu DC, Chan KH, Kung MH, Ramsden DB, Ho SL: Transcriptional regulation of UCP4 by NF-kappaB and its role in mediating protection against MPP+ toxicity. Free Radic Biol Med 2010, 49:192-204.
• [93]Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, et al.: A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol 2004, 6:97-105.
• [94]Widera D, Mikenberg I, Elvers M, Kaltschmidt C, Kaltschmidt B: Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-kappaB signaling. BMC Neurosci 2006, 7:64.
• [95]Pawade T, Ho PW, Kwok KH, Chu AC, Ho SL, Ramsden DB: Uncoupling proteins: targets of endocrine disruptors? Mol Cell Endocrinol 2005, 244:79-86.
• [96]Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, McDonagh T, Lemieux M, McBurney M, Szilvasi A, et al.: Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 2006, 4:e31.
• [97]Dietrich MO, Horvath TL: The role of mitochondrial uncoupling proteins in lifespan. Pflugers Arch 2010, 459:269-275.
• [98]Liu Y, Chen L, Xu X, Vicaut E, Sercombe R: Both ischemic preconditioning and ghrelin administration protect hippocampus from ischemia/reperfusion and upregulate uncoupling protein-2. BMC Physiol 2009, 9:17.
• [99]Ridder DA, Schwaninger M: NF-kappaB signaling in cerebral ischemia. Neuroscience 2009, 158:995-1006.
• [100]Yang L, Tao LY, Chen XP: Roles of NF-kappaB in central nervous system damage and repair. Neurosci Bull 2007, 23:307-313.
• [101]Sarnico I, Lanzillotta A, Benarese M, Alghisi M, Baiguera C, Battistin L, Spano P, Pizzi M: NF-kappaB dimers in the regulation of neuronal survival. Int Rev Neurobiol 2009, 85:351-362.
• [102]Memet S: NF-kappaB functions in the nervous system: from development to disease. Biochem Pharmacol 2006, 72:1180-1195.
• [103]Mattson MP, Meffert MK: Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ 2006, 13:852-860.
• [104]Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB: Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 2004, 88:494-501.
• [105]Hunot S, Brugg B, Ricard D, Michel PP, Muriel MP, Ruberg M, Faucheux BA, Agid Y, Hirsch EC: Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with parkinson disease. Proc Natl Acad Sci USA 1997, 94:7531-7536.
• [106]Soos J, Engelhardt JI, Siklos L, Havas L, Majtenyi K: The expression of PARP, NF-kappa B and parvalbumin is increased in Parkinson disease. Neuroreport 2004, 15:1715-1718.
• [107]Tarabin V, Schwaninger M: The role of NF-kappaB in 6-hydroxydopamine- and TNFalpha-induced apoptosis of PC12 cells. Naunyn Schmiedebergs Arch Pharmacol 2004, 369:563-569.
• [108]Szolnoki Z, Kondacs A, Mandi Y, Bodor A, Somogyvari F: A homozygous genetic variant of mitochondrial uncoupling protein 4 exerts protection against the occurrence of multiple sclerosis. Neuromolecular Med 2009, 11:101-105.
• [109]Mouaffak F, Kebir O, Bellon A, Gourevitch R, Tordjman S, Viala A, Millet B, Jaafari N, Olie JP, Krebs MO: Association of an UCP4 (SLC25A27) haplotype with ultra-resistant schizophrenia. Pharmacogenomics 2011, 12:185-193.
• [110]Yasuno K, Ando S, Misumi S, Makino S, Kulski JK, Muratake T, Kaneko N, Amagane H, Someya T, Inoko H, et al.: Synergistic association of mitochondrial uncoupling protein (UCP) genes with schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2007, 144B:250-253.
• [111]Szolnoki Z: Common genetic variants of the mitochondrial trafficking system and mitochondrial uncoupling proteins affect the development of two slowly developing demyelinating disorders, leukoaraiosis and multiple sclerosis. Curr Med Chem 2010, 17:3583-3590.
• [112]Wu Z, Zhao Y, Zhao B: Superoxide anion, uncoupling proteins and Alzheimer's disease. J Clin Biochem Nutr 2010, 46:187-194.