Abstract
Alzheimer’s disease (AD) is a complex brain disorder of the limbic system and association cortices. The disease is characterized by the production and deposition of the amyloid β-peptide (Aβ) in the brain, and the neuropathological mechanisms involved must be deciphered to gain further insights into the fundamental aspects of the protein biology responsible for the development and progression of this disease. Aβ is generated by the intramembranous cleavage of the β-amyloid precursor protein, which is mediated by the proteases β- and γ-secretase. Accumulating evidence suggests the importance of the coupling of this cleavage mechanism to G protein signaling. Heterotrimeric G proteins play pivotal roles as molecular switches in signal transduction pathways mediated by G protein-coupled receptors (GPCRs). Extracellular stimuli activate these receptors, which in turn catalyze guanosine triphosphate–guanosine diphosphate exchange on the G protein α-subunit. The activation–deactivation cycles of G proteins underlie their crucial functions as molecular switches for a vast array of biological responses. The novel transcription regulator protein p60 transcription regulator protein and its related GPCR signaling pathways have recently been described as potential targets for the development of alternative strategies for inhibiting the early signaling mechanisms involved in neurodegenerative diseases such as AD.
Similar content being viewed by others
References
Maurer K, Volk S, Gerbaldo H (1997) Auguste D and Alzheimer’s disease. Lancet 349:1546–1549
Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An English translation of Alzheimer’s 1907 paper, “Über eine eigenartige Erkankung der Hirnrinde”. Clin Anat 8:429–431
Heese K, Akatsu H (2006) Alzheimer’s disease—an interactive perspective. Curr Alzheimer Res 3:109–121
Graeber MB, Kosel S, Egensperger R, Banati RB, Muller U, Bise K, Hoff P, Moller HJ, Fujisawa K, Mehraein P (1997) Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis. Neurogenetics 1:73–80
Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639
Selkoe DJ, Schenk D (2003) Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 43:545–584
Goedert M, Klug A, Crowther RA (2006) Tau protein, the paired helical filament and Alzheimer’s disease. J Alzheimers Dis 9:195–207
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356
Palop JJ, Mucke L (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818
Lee VM (2001) Biomedicine. Tauists and beta-aptists united—well almost! Science 293:1446–1447
Heese K, Yamada T, Akatsu H, Yamamoto T, Kosaka K, Nagai Y, Sawada T (2004) Characterizing the new transcription regulator protein p60TRP. J Cell Biochem 91:1030–1042
Neves SR, Ram PT, Iyengar R (2002) G protein pathways. Science 296:1636–1639
Cabrera-Vera TM, Vanhauwe J, Thomas TO, Medkova M, Preininger A, Mazzoni MR, Hamm HE (2003) Insights into G protein structure, function, and regulation. Endocr Rev 24:765–781
Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Murayama Y, Ogata E (1993) Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o). Nature 362:75–79
Ikezu T, Okamoto T, Komatsuzaki K, Matsui T, Martyn JA, Nishimoto I (1996) Negative transactivation of cAMP response element by familial Alzheimer’s mutants of APP. EMBO J 15:2468–2475
Yamatsuji T, Matsui T, Okamoto T, Komatsuzaki K, Takeda S, Fukumoto H, Iwatsubo T, Suzuki N, Asami-Odaka A, Ireland S, Kinane TB, Giambarella U, Nishimoto I (1996) G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer’s disease-associated mutants of APP. Science 272:1349–1352
Giambarella U, Murayama Y, Ikezu T, Fujita T, Nishimoto I (1997) Potential CRE suppression by familial Alzheimer’s mutants of APP independent of adenylyl cyclase regulation. FEBS Lett 412:97–101
Giambarella U, Yamatsuji T, Okamoto T, Matsui T, Ikezu T, Murayama Y, Levine MA, Katz A, Gautam N, Nishimoto I (1997) G protein betagamma complex-mediated apoptosis by familial Alzheimer’s disease mutant of APP. EMBO J 16:4897–4907
Nishimoto I (1998) A new paradigm for neurotoxicity by FAD mutants of betaAPP: a signaling abnormality. Neurobiol Aging 19:S33–S38
Shaked GM, Chauv S, Ubhi K, Hansen LA, Masliah E (2009) Interactions between the amyloid precursor protein C-terminal domain and G proteins mediate calcium dysregulation and amyloid beta toxicity in Alzheimer’s disease. FEBS J 276:2736–2751
Thathiah A, De Strooper B (2009) G protein-coupled receptors, cholinergic dysfunction, and Abeta toxicity in Alzheimer’s disease. Sci Signal 2:re8
Bakshi P, Jin C, Broutin P, Berhane B, Reed J, Mullan M (2009) Structural optimization of a CXCR2-directed antagonist that indirectly inhibits gamma-secretase and reduces Abeta. Bioorg Med Chem 17:8102–8112
Teng L, Zhao J, Wang F, Ma L, Pei G (2010) A GPCR/secretase complex regulates beta- and gamma-secretase specificity for Abeta production and contributes to AD pathogenesis. Cell Res 20:138–153
Thathiah A, De Strooper B (2011) The role of G protein-coupled receptors in the pathology of Alzheimer’s disease. Nat Rev Neurosci 12:73–87
Jiang Y, Mullaney KA, Peterhoff CM, Che S, Schmidt SD, Boyer-Boiteau A, Ginsberg SD, Cataldo AM, Mathews PM, Nixon RA (2010) Alzheimer’s-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition. Proc Natl Acad Sci USA 107:1630–1635
Ginsberg SD, Mufson EJ, Counts SE, Wuu J, Alldred MJ, Nixon RA, Che S (2010) Regional selectivity of rab5 and rab7 protein upregulation in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 22:631–639
Li G (2011) Rab GTPases, membrane trafficking and diseases. Curr Drug Targets 12:1188–1193
Kimura N, Inoue M, Okabayashi S, Ono F, Negishi T (2009) Dynein dysfunction induces endocytic pathology accompanied by an increase in Rab GTPases: a potential mechanism underlying age-dependent endocytic dysfunction. J Biol Chem 284:31291–31302
Kimura N, Okabayashi S, Ono F (2012) Dynein dysfunction disrupts intracellular vesicle trafficking bidirectionally and perturbs synaptic vesicle docking via endocytic disturbances a potential mechanism underlying age-dependent impairment of cognitive function. Am J Pathol 180:550–561
Mieda M, Sakurai T (2009) Integrative physiology of orexins and orexin receptors. CNS Neurol Disord Drug Targets 8:281–295
Kodadek T, Cai D (2010) Chemistry and biology of orexin signaling. Mol Biosyst 6:1366–1375
Matsuki T, Sakurai T (2008) Orexins and orexin receptors: from molecules to integrative physiology. Results Probl Cell Differ 46:27–55
Sakurai T, Mieda M, Tsujino N (2010) The orexin system: roles in sleep/wake regulation. Ann N Y Acad Sci 1200:149–161
Gatfield J, Brisbare-Roch C, Jenck F, Boss C (2010) Orexin receptor antagonists: a new concept in CNS disorders? ChemMedChem 5:1197–1214
Winrow CJ, Tanis KQ, Reiss DR, Rigby AM, Uslaner JM, Uebele VN, Doran SM, Fox SV, Garson SL, Gotter AL, Levine DM, Roecker AJ, Coleman PJ, Koblan KS, Renger JJ (2010) Orexin receptor antagonism prevents transcriptional and behavioral plasticity resulting from stimulant exposure. Neuropharmacology 58:185–194
Coleman PJ, Renger JJ (2010) Orexin receptor antagonists: a review of promising compounds patented since 2006. Expert Opin Ther Pat 20:307–324
Roos RA, Aziz NA (2007) Hypocretin-1 and secondary signs in Huntington’s disease. Parkinsonism Relat Disord 13:S387–S390
Aziz A, Fronczek R, Maat-Schieman M, Unmehopa U, Roelandse F, Overeem S, van Duinen S, Lammers GJ, Swaab D, Roos R (2008) Hypocretin and melanin-concentrating hormone in patients with Huntington disease. Brain Pathol 18:474–483
Baumann CR, Hersberger M, Bassetti CL (2006) Hypocretin-1 (orexin A) levels are normal in Huntington’s disease. J Neurol 253:1232–1233
Meier A, Mollenhauer B, Cohrs S, Rodenbeck A, Jordan W, Meller J, Otto M (2005) Normal hypocretin-1 (orexin-A) levels in the cerebrospinal fluid of patients with Huntington’s disease. Brain Res 1063:201–203
Thannickal TC, Lai YY, Siegel JM (2007) Hypocretin (orexin) cell loss in Parkinson’s disease. Brain 130:1586–1595
Fronczek R, Overeem S, Lee SY, Hegeman IM, van Pelt J, van Duinen SG, Lammers GJ, Swaab DF (2007) Hypocretin (orexin) loss in Parkinson’s disease. Brain 130:1577–1585
Yasui K, Inoue Y, Kanbayashi T, Nomura T, Kusumi M, Nakashima K (2006) CSF orexin levels of Parkinson’s disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration. J Neurol Sci 250:120–123
Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM (2009) Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326:1005–1007
Abu-Helo A, Simonin F (2010) Identification and biological significance of G protein-coupled receptor associated sorting proteins (GASPs). Pharmacol Ther 126:244–250
Moser E, Kargl J, Whistler JL, Waldhoer M, Tschische P (2010) G protein-coupled receptor-associated sorting protein 1 regulates the postendocytic sorting of seven-transmembrane-spanning g protein-coupled receptors. Pharmacology 86:22–29
Mishra M, Heese K (2011) P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and synaptogenesis. J Cell Mol Med 15:2462–2477
Matsuki T, Kiyama A, Kawabuchi M, Okada M, Nagai K (2001) A novel protein interacts with a clock-related protein, rPer1. Brain Res 916:1–10
Kiyama A, Isojima Y, Nagai K (2006) Role of Per1-interacting protein of the suprachiasmatic nucleus in NGF mediated neuronal survival. Biochem Biophys Res Commun 339:514–519
Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao J, Shan WS, Myszka DG, Shapiro L (2001) G-protein signaling through tubby proteins. Science 292:2041–2050
White JH, McIllhinney RA, Wise A, Ciruela F, Chan WY, Emson PC, Billinton A, Marshall FH (2000) The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx. Proc Natl Acad Sci USA 97:13967–13972
Nagoshi E, Yoneda Y (2001) Dimerization of sterol regulatory element-binding protein 2 via the helix-loop-helix-leucine zipper domain is a prerequisite for its nuclear localization mediated by importin beta. Mol Cell Biol 21:2779–2789
Zinser EG, Hartmann T, Grimm MO (2007) Amyloid beta-protein and lipid metabolism. Biochim Biophys Acta 1768:1991–2001
Uyeda K, Yamashita H, Kawaguchi T (2002) Carbohydrate responsive element-binding protein (ChREBP): a key regulator of glucose metabolism and fat storage. Biochem Pharmacol 63:2075–2080
Dentin R, Girard J, Postic C (2005) Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie 87:81–86
Sorkin A, Von Zastrow M (2002) Signal transduction and endocytosis: close encounters of many kinds. Nat Rev Mol Cell Biol 3:600–614
Pierce KL, Lefkowitz RJ (2001) Classical and new roles of beta-arrestins in the regulation of G-protein-coupled receptors. Nat Rev Neurosci 2:727–733
Pierce KL, Premont RT, Lefkowitz RJ (2002) Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3:639–650
Winter EE, Ponting CP (2005) Mammalian BEX, WEX and GASP genes: coding and non-coding chimaerism sustained by gene conversion events. BMC Evol Biol 5:54
Vilar M, Murillo-Carretero M, Mira H, Magnusson K, Besset V, Ibanez CF (2006) Bex1, a novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle. EMBO J 25:1219–1230
Ding K, Su Y, Pang L, Lu Q, Wang Z, Zhang S, Zheng S, Mao J, Zhu Y (2009) Inhibition of apoptosis by downregulation of hBex1, a novel mechanism, contributes to the chemoresistance of Bcr/Abl + leukemic cells. Carcinogenesis 30:35–42
Khazaei MR, Halfter H, Karimzadeh F, Koo JH, Margolis FL, Young P (2010) Bex1 is involved in the regeneration of axons after injury. J Neurochem 115:910–920
Carney DS, Davies BA, Horazdovsky BF (2006) Vps9 domain-containing proteins: activators of Rab5 GTPases from yeast to neurons. Trends Cell Biol 16:27–35
Galvis A, Giambini H, Villasana Z, Barbieri MA (2009) Functional determinants of ras interference 1 mutants required for their inhibitory activity on endocytosis. Exp Cell Res 315:820–835
Galvis A, Balmaceda V, Giambini H, Conde A, Villasana Z, Fornes MW, Barbieri MA (2009) Inhibition of early endosome fusion by Rab5-binding defective Ras interference 1 mutants. Arch Biochem Biophys 482:83–95
Kong C, Su X, Chen PI, Stahl PD (2007) Rin1 interacts with signal-transducing adaptor molecule (STAM) and mediates epidermal growth factor receptor trafficking and degradation. J Biol Chem 282:15294–15301
Bliss JM, Gray EE, Dhaka A, O’Dell TJ, Colicelli J (2010) Fear learning and extinction are linked to neuronal plasticity through Rin1 signaling. J Neurosci Res 88:917–926
Dzudzor B, Huynh L, Thai M, Bliss JM, Nagaoka Y, Wang Y, Ch’ng TH, Jiang M, Martin KC, Colicelli J (2010) Regulated expression of the Ras effector Rin1 in forebrain neurons. Mol Cell Neurosci 43:108–116
Wang Y, Waldron RT, Dhaka A, Patel A, Riley MM, Rozengurt E, Colicelli J (2002) The RAS effector RIN1 directly competes with RAF and is regulated by 14-3-3 proteins. Mol Cell Biol 22:916–926
Dhaka A, Costa RM, Hu H, Irvin DK, Patel A, Kornblum HI, Silva AJ, O’Dell TJ, Colicelli J (2003) The RAS effector RIN1 modulates the formation of aversive memories. J Neurosci 23:748–757
Deininger K, Eder M, Kramer ER, Zieglgansberger W, Dodt HU, Dornmair K, Colicelli J, Klein R (2008) The Rab5 guanylate exchange factor Rin1 regulates endocytosis of the EphA4 receptor in mature excitatory neurons. Proc Natl Acad Sci USA 105:12539–12544
Manavalan M, Mishra M, Sze SK, Heese K (2013) Brain-site-specific proteome changes induced by neuronal p60TRP expression. Neurosignals. doi:10.1159/000343672
Woscholski R, Finan PM, Radley E, Totty NF, Sterling AE, Hsuan JJ, Waterfield MD, Parker PJ (1997) Synaptojanin is the major constitutively active phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase in rodent brain. J Biol Chem 272:9625–9628
Lee SY, Wenk MR, Kim Y, Nairn AC, De Camilli P (2004) Regulation of synaptojanin 1 by cyclin-dependent kinase 5 at synapses. Proc Natl Acad Sci USA 101:546–551
Voronov SV, Frere SG, Giovedi S, Pollina EA, Borel C, Zhang H, Schmidt C, Akeson EC, Wenk MR, Cimasoni L, Arancio O, Davisson MT, Antonarakis SE, Gardiner K, De Camilli P, Di Paolo G (2008) Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down’s syndrome. Proc Natl Acad Sci USA 105:9415–9420
Saito T, Guan F, Papolos DF, Lau S, Klein M, Fann CS, Lachman HM (2001) Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder. Mol Psychiatry 6:387–395
Vazquez-Higuera JL, Mateo I, Sanchez-Juan P, Rodriguez-Rodriguez E, Pozueta A, Calero M, Dobato JL, Frank-Garcia A, Valdivieso F, Berciano J, Bullido MJ, Combarros O (2011) Genetic variation in the tau protein phosphatase-2A pathway is not associated with Alzheimer’s disease risk. BMC Res Notes 4:327
Iqbal K, Wang X, Blanchard J, Liu F, Gong CX, Grundke-Iqbal I (2010) Alzheimer’s disease neurofibrillary degeneration: pivotal and multifactorial. Biochem Soc Trans 38:962–966
Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118:53–69
Qian W, Shi J, Yin X, Iqbal K, Grundke-Iqbal I, Gong CX, Liu F (2010) PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta. J Alzheimers Dis 19:1221–1229
Nagai Y, Ogasawara A, Heese K (2004) Possible mechanisms of A beta(1-40)- or A beta(1-42)-induced cell death and their rescue factors. Nihon Yakurigaku Zasshi 124:135–143
He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (2010) Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature 467:95–98
Bellucci A, Navarria L, Zaltieri M, Missale C, Spano P (2012) Alpha-synuclein synaptic pathology and its implications in the development of novel therapeutic approaches to cure Parkinson’s disease. Brain Res 1432:95–113
Schulz-Schaeffer WJ (2010) The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia. Acta Neuropathol 120:131–143
Yasuda T, Mochizuki H (2010) The regulatory role of alpha-synuclein and parkin in neuronal cell apoptosis; possible implications for the pathogenesis of Parkinson’s disease. Apoptosis 15:1312–1321
Cheng F, Li X, Li Y, Wang C, Wang T, Liu G, Baskys A, Ueda K, Chan P, Yu S (2011) alpha-Synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death. J Neurochem 119:815–825
Sherer TB, Betarbet R, Greenamyre JT (2001) Pathogenesis of Parkinson’s disease. Curr Opin Investig Drugs 2:657–662
Huls S, Hogen T, Vassallo N, Danzer KM, Hengerer B, Giese A, Herms J (2011) AMPA-receptor-mediated excitatory synaptic transmission is enhanced by iron-induced alpha-synuclein oligomers. J Neurochem 117:868–878
Anwar S, Peters O, Millership S, Ninkina N, Doig N, Connor-Robson N, Threlfell S, Kooner G, Deacon RM, Bannerman DM, Bolam JP, Chandra SS, Cragg SJ, Wade-Martins R, Buchman VL (2011) Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family. J Neurosci 31:7264–7274
Varkey J, Isas JM, Mizuno N, Jensen MB, Bhatia VK, Jao CC, Petrlova J, Voss JC, Stamou DG, Steven AC, Langen R (2010) Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins. J Biol Chem 285:32486–32493
Beyer K, Ispierto L, Latorre P, Tolosa E, Ariza A (2011) Alpha- and beta-synuclein expression in Parkinson disease with and without dementia. J Neurol Sci 310:112–117
Beyer K, Munoz-Marmol AM, Sanz C, Marginet-Flinch R, Ferrer I, Ariza A (2012) New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases. Neurogenetics 13:61–72
Shaltiel-Karyo R, Frenkel-Pinter M, Egoz-Matia N, Frydman-Marom A, Shalev DE, Segal D, Gazit E (2010) Inhibiting alpha-synuclein oligomerization by stable cell-penetrating beta-synuclein fragments recovers phenotype of Parkinson’s disease model flies. PLoS One 5:e13863
Jabbari K, Bernardi G (2004) Cytosine methylation and CpG, TpG (CpA) and TpA frequencies. Gene 333:143–149
Jacinto FV, Ballestar E, Ropero S, Esteller M (2007) Discovery of epigenetically silenced genes by methylated DNA immunoprecipitation in colon cancer cells. Cancer Res 67:11481–11486
Acknowledgments
This study was supported by the Hanyang University, Seoul, Republic of Korea.
Conflict of interest
KH declares no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Heese, K. G Proteins, p60TRP, and Neurodegenerative Diseases. Mol Neurobiol 47, 1103–1111 (2013). https://doi.org/10.1007/s12035-013-8410-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-013-8410-1