Fragile X syndrome (Homo sapiens)

From WikiPathways

Revision as of 21:38, 17 May 2021 by Eweitz (Talk | contribs)
Jump to: navigation, search
P3238393427202295798782223716382282797683794144922391413, 1758797679768124, 40237941235924544740599236403567679889124582333, 913623699247934780941252565, 794847502541NMDARsubunitsNMDARinternalizationFXS:loss of FMRPOther targetsAnterior cingulate cortexDefective cAMP productionstalled polyribosomesBasolateral AmygdalaNMDA ReceptorPoolGABA A Receptor Subunits2675RISC ComplexGABAergic synapse components59Dysregulated metabolic homeostasis53, 97TSC complex PKAeIF4F complexmGluR-LTD35Receptor subunitsHippocampus CA190AMPA ReceptorEnteric innervation of the ileum42upregulationTrkB ReceptorLTD proteins160ClathrinNMDA ReceptorAMPAR internalizationAMPA Receptor PoolDysregulation of GABAergic synaptic transmissiondeletionrelease of Ca2+Lipid and glucose metabolsim53AP-2Group I mGluR47mTORC170GDPMMP9KCNC1HCN1SRCHOMER1FYNGRM5glutamateGRIN2ADUSP3BDNF-TrkB SignallingCNR1GRIN2AEPS8L1EEF1A1CYFIP2GABRDKCND2494ABAT64PI3K-Akt-mTOR Pathway19CAMKIV-CREB PathwayglutamateBDNFAP2A1PLCB1GAD1cAMPCLTCL1PPP3CAGRIP2CREB1DLG4DLG42, 16SLC6A157PRKCAGAD114PRKACAMEK-ERK-Mnk1 Pathway19EIF4G1ALDH5A111γ-aminobutyric acid73SHC1GRIA1CLTCAP2B1CPT1APRKACAPIP2PTPN5GRB2CLTBGPHN77GRIP1DLG4GRIA2APPmiR-125bCAMK4CREB1PTPN11GRIA1AP2S1AGO2AKAP546GABRG2CAMK1ARHGAP3210GAB1GABRA1PTPN53, 33Dynamin-1DICER16AP2M1PICK1DAG1GRIN2B76, 82GABRB2endocannabinoidsNTRK2SLC16A1CLTAGRIA2SYNGAP1ITPR1PPP1CA51PLCG1CAMK2BSHANK1DLG4DLGAP3MAP2K2FMR13MAP1BARCMKNK1RPS6KB1MAP1B3MAPK1KRASCYFIP112AKT1S1ARC52MAP2K1CAMK2ASOS113PPP2R5BEIF4EBP2RAF1NF115EIF4ECAMK2A72, 87FMR1DEPTORTELO2RPTORMLST8MTORPIK3CBTTI1GRM5RHEBHOMER1GRM1PDK1AGAP2PIP2PTENTSC1AKT1PIP3TSC2TBC1D7RHEBGTPP at Ser500KRASGDPGTPPPPPPDLGAP329, 89SHANK162GRIN2BGRIN2B31GABRA1GABRB2GABRG2GPHNSLC6A1ABATALDH5A1ALDH3A2ABCD3TECRCPT1A53, 67SLC16A153ALDH3A253, 55ABCD366TECR96PPRKAR1APRKAR1APFMR1Influx Ca2+GRIA1GRIA2AMPA ReceptorPGRIA2GRIA146GRIA1GRIA2miR-132miR-196aSH3GL1DNM217260360PP at Thr308EIF4A1TARBP2EIF4EBP254MECP274EPHA41GRIN2ACDKN2AHOXB8MAP2K2MAP2K1MAPK1MKNK1BRAFARAFPSH3GL3mGluR-LTPAMPA ReceptorAMPAR exocytosis46730385downregulation535353NMDARLTD61PKAPRKACAPRKACAPRKAR1APRKAR1AAPP21, 4534Cerebellar cortex43Amygdala23, 42, 94Corticostriatal synapse42Neocortical layer5 neurons42Audiogenic seizures42C-fiber innervation42Suprachiasmatic nucleus42372133GRIN2B76P at Y1472PAP-2AP2A1AP2B1AP2S1AP2M1ClathrinCLTCL1CLTCCLTB22CLTAGRIN2B76overactivationSomatosensoryCortexStriatumSubiculum Hippocampus CA1PTENPTEN6868GRIN1GRIN1DUSP38686NMDARLTPNMDARintsertionEEF1A1CYFIP2GABRD34GRM5HCN1KCNC1KCND2MMP9PRKCAPPRAP1GAP18, 84PEPS8L1P85SHANK162PTPN5MAP1B3, 333PTPN5DUSP33, 3386hypofunction


Description

Fragile X syndrome (FXS) is a monogenetic disorder cause by a mutation in the FMR1 gene and the most common form of inherited intellectual disability and autism spectrum disorder (ASD). Patients with FXS show a range of typical physical features such as macro-orchidism in males, a long and narrow face, large and protruding ears and hyperextensible joints. Common comorbidities of FXS are neuropsychiatric disorders such as hyperactivity, depression and anxiety. The mutation of FMR1 in FXS disrupts production of the FMR1 gene product, the fragile mental retardation protein (FMRP). The main function of FMRP is to locally act as a translational repressor for target mRNAs and thereby regulate de novo protein synthesis and ultimately synaptic plasticity. FMRP, together with the mTOR pathway and the ERK pathway regulates expression of target mRNAsn mediated by stimulation of Group I metabotropic glutamate receptors (mGluR) and thereby regulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalisation and thus long term depression (LTD). LTD is a form of synaptic plasticity which is involved in learning and memory. Lack of FMRP leads to exaggerated mGluR dependant LTD, which accounts for most of FXS pathogenesis.

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Zhang L, Alger BE; ''Enhanced endocannabinoid signaling elevates neuronal excitability in fragile X syndrome.''; J Neurosci, 2010 PubMed Europe PMC Scholia
  2. Yau SY, Bettio L, Chiu J, Chiu C, Christie BR; ''Fragile-X Syndrome Is Associated With NMDA Receptor Hypofunction and Reduced Dendritic Complexity in Mature Dentate Granule Cells.''; Front Mol Neurosci, 2018 PubMed Europe PMC Scholia
  3. Karsten Schmidt; ''Analysis of the Structure and Function of Protein Phosphatase 2A ''; http://edoc.unibas.ch/diss/DissB_6695; Institutional Repository of the University of Basel, 2004 DOI Scholia
  4. Denise Cook, Scott A. Cameron, Emma V. Jones; ''Fragile X Mental Retardation Protein: Regulator of Specific mRNAs or Master Regulator of Global Translation?''; Google Scholar, 2010 PubMed Europe PMC Scholia
  5. Boykevisch S, Zhao C, Sondermann H, Philippidou P, Halegoua S, Kuriyan J, Bar-Sagi D; ''Regulation of ras signaling dynamics by Sos-mediated positive feedback.''; Curr Biol, 2006 PubMed Europe PMC Scholia
  6. Liu B, Li L, Chen J, Wang Z, Li Z, Wan Q; ''Regulation of GABAA receptors by fragile X mental retardation protein.''; Int J Physiol Pathophysiol Pharmacol, 2013 PubMed Europe PMC Scholia
  7. Hanley JG; ''The Regulation of AMPA Receptor Endocytosis by Dynamic Protein-Protein Interactions.''; Front Cell Neurosci, 2018 PubMed Europe PMC Scholia
  8. Yoshii A, Constantine-Paton M; ''Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease.''; Dev Neurobiol, 2010 PubMed Europe PMC Scholia
  9. Lüscher C, Malenka RC; ''NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD).''; Cold Spring Harb Perspect Biol, 2012 PubMed Europe PMC Scholia
  10. Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N, Kuhl D, Huganir RL, Worley PF; ''Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking.''; Neuron, 2006 PubMed Europe PMC Scholia
  11. Hu X, Wu X, Xu J, Zhou J, Han X, Guo J; ''Src kinase up-regulates the ERK cascade through inactivation of protein phosphatase 2A following cerebral ischemia.''; BMC Neurosci, 2009 PubMed Europe PMC Scholia
  12. Sabiha Abekhoukh, H. Bahar Sahin, Mauro Grossi, Samantha Zongaro, Thomas Maurin, Irene Madrigal, Daniele Kazue-Sugioka, Annick Raas-Rothschild, Mohamed Doulazmi, Pilar Carrera, Andrea Stachon, Steven Scherer, Maria Rita Drula Do Nascimento, Alain Trembleau, Ignacio Arroyo, Peter Szatmari, Isabel M. Smith, Montserrat Milà, Adam C. Smith, Angela Giangrande, Isabelle Caillé, Barbara Bardoni; ''New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes''; Google Scholar, 2017 PubMed Europe PMC Scholia
  13. Robert B. Denman; ''Modeling Fragile X Syndrome''; Springer Books, 2011
  14. Delghandi MP, Johannessen M, Moens U; ''The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells.''; Cell Signal, 2005 PubMed Europe PMC Scholia
  15. LF Reichard; ''Neurotrophin-regulated signalling pathways''; Philos Trans R Soc Lond B Biol Sci, 2006 PubMed Europe PMC Scholia
  16. Marko Kaksonen, Aurélien Roux; ''Mechanisms of clathrin-mediated endocytosis''; Nature, 2018 PubMed Europe PMC Scholia
  17. Katarzyna Switona, Katarzyna Kotulskab, Aleksandra Janusz-Kaminskaa, Justyna Zmorzynskaa, Jacek Jaworski; ''Molecular Neurobiology of mTOR''; Google Scholar, 2017 PubMed Europe PMC Scholia
  18. Ceman S, O'Donnell WT, Reed M, Patton S, Pohl J, Warren ST; ''Phosphorylation influences the translation state of FMRP-associated polyribosomes.''; Hum Mol Genet, 2003 PubMed Europe PMC Scholia
  19. Robert Malenka; ''Intercellular Communication in the Nervous System''; Google Books, 2010
  20. Kim SH, Markham JA, Weiler IJ, Greenough WT; ''Aberrant early-phase ERK inactivation impedes neuronal function in fragile X syndrome.''; Proc Natl Acad Sci U S A, 2008 PubMed Europe PMC Scholia
  21. Luo J, Manning BD, Cantley LC; ''Targeting the PI3K-Akt pathway in human cancer: rationale and promise.''; Cancer Cell, 2003 PubMed Europe PMC Scholia
  22. Ishizuka A, Siomi MC, Siomi H; ''A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins.''; Genes Dev, 2002 PubMed Europe PMC Scholia
  23. Ronesi JA, Collins KA, Hays SA, Tsai NP, Guo W, Birnbaum SG, Hu JH, Worley PF, Gibson JR, Huber KM; ''Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome.''; Nat Neurosci, 2012 PubMed Europe PMC Scholia
  24. Avruch J, Khokhlatchev A, Kyriakis JM, Luo Z, Tzivion G, Vavvas D, Zhang XF; ''Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade.''; Recent Prog Horm Res, 2001 PubMed Europe PMC Scholia
  25. Guo W, Ceolin L, Collins KA, Perroy J, Huber KM; ''Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model.''; Cell Rep, 2015 PubMed Europe PMC Scholia
  26. Joseph Vithayathil, Joanna Pucilowska, Gary E. Landreth; ''ERK/MAPK signaling and autism spectrum disorders''; ScienceDirect, 2018 PubMed Europe PMC Scholia
  27. Plotnikov A, Zehorai E, Procaccia S, Seger R; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; Biochim Biophys Acta, 2011 PubMed Europe PMC Scholia
  28. Westmark CJ, Malter JS; ''FMRP mediates mGluR5-dependent translation of amyloid precursor protein.''; PLoS Biol, 2007 PubMed Europe PMC Scholia
  29. Bhakar AL, Dölen G, Bear MF; ''The pathophysiology of fragile X (and what it teaches us about synapses).''; Annu Rev Neurosci, 2012 PubMed Europe PMC Scholia
  30. Ronesi JA, Huber KM; ''Homer interactions are necessary for metabotropic glutamate receptor-induced long-term depression and translational activation.''; J Neurosci, 2008 PubMed Europe PMC Scholia
  31. Chen BS, Roche KW; ''Regulation of NMDA receptors by phosphorylation.''; Neuropharmacology, 2007 PubMed Europe PMC Scholia
  32. Lu W, Ziff EB; ''PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking.''; Neuron, 2005 PubMed Europe PMC Scholia
  33. Li Y, Tang W, Zhang LR, Zhang CY; ''FMRP regulates miR196a-mediated repression of HOXB8 via interaction with the AGO2 MID domain.''; Mol Biosyst, 2014 PubMed Europe PMC Scholia
  34. Sethna F, Moon C, Wang H; ''From FMRP function to potential therapies for fragile X syndrome.''; Neurochem Res, 2014 PubMed Europe PMC Scholia
  35. Lai MM, Hong JJ, Ruggiero AM, Burnett PE, Slepnev VI, De Camilli P, Snyder SH; ''The calcineurin-dynamin 1 complex as a calcium sensor for synaptic vesicle endocytosis.''; J Biol Chem, 1999 PubMed Europe PMC Scholia
  36. Paradee W, Melikian HE, Rasmussen DL, Kenneson A, Conn PJ, Warren ST; ''Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function.''; Neuroscience, 1999 PubMed Europe PMC Scholia
  37. Lüscher C, Huber KM; ''Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease.''; Neuron, 2010 PubMed Europe PMC Scholia
  38. Wang H, Kim SS, Zhuo M; ''Roles of fragile X mental retardation protein in dopaminergic stimulation-induced synapse-associated protein synthesis and subsequent alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-4-propionate (AMPA) receptor internalization.''; J Biol Chem, 2010 PubMed Europe PMC Scholia
  39. Ye K, Snyder SH; ''PIKE GTPase: a novel mediator of phosphoinositide signaling.''; J Cell Sci, 2004 PubMed Europe PMC Scholia
  40. Weerasak Chonchaiya, Andrea Schneider, Randi J Hagerman; ''Fragile X: A Family of Disorders''; doi:10.1016/j.yapd.2009.08.008, 2010 PubMed Europe PMC Scholia
  41. Xing Liu, Qin-Hua Gu, Kaizheng Duan, Zheng Li; ''NMDA Receptor-Dependent LTD Is Required for Consolidation But Not Acquisition of Fear Memory''; The Journal of Neurosicence, 2014 PubMed Europe PMC Scholia
  42. Liu B, Li L, Chen J, Wang Z, Li Z, Wan Q; ''Regulation of GABAA receptors by fragile X mental retardation protein.''; Int J Physiol Pathophysiol Pharmacol, 2013 PubMed Europe PMC Scholia
  43. Kim SW, Cho KJ; ''Activity-dependent alterations in the sensitivity to BDNF-TrkB signaling may promote excessive dendritic arborization and spinogenesis in fragile X syndrome in order to compensate for compromised postsynaptic activity.''; Med Hypotheses, 2014 PubMed Europe PMC Scholia
  44. Bagni C, Tassone F, Neri G, Hagerman R; ''Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics.''; J Clin Invest, 2012 PubMed Europe PMC Scholia
  45. Hou L, Antion MD, Hu D, Spencer CM, Paylor R, Klann E; ''Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression.''; Neuron, 2006 PubMed Europe PMC Scholia
  46. Narayanan U, Nalavadi V, Nakamoto M, Thomas G, Ceman S, Bassell GJ, Warren ST; ''S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade.''; J Biol Chem, 2008 PubMed Europe PMC Scholia
  47. Uzunova G, Hollander E, Shepherd J; ''The role of ionotropic glutamate receptors in childhood neurodevelopmental disorders: autism spectrum disorders and fragile x syndrome.''; Curr Neuropharmacol, 2014 PubMed Europe PMC Scholia
  48. Jacinto E, Hall MN; ''Tor signalling in bugs, brain and brawn.''; Nat Rev Mol Cell Biol, 2003 PubMed Europe PMC Scholia
  49. Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H; ''GABA and GABA receptors in the central nervous system and other organs.''; Int Rev Cytol, 2002 PubMed Europe PMC Scholia
  50. Gao F, Qi L, Yang Z, Yang T, Zhang Y, Xu H, Zhao H; ''Impaired GABA Neural Circuits Are Critical for Fragile X Syndrome.''; Neural Plast, 2018 PubMed Europe PMC Scholia
  51. DaSilva LL, Wall MJ, P de Almeida L, Wauters SC, Januário YC, Müller J, Corrêa SA; ''Activity-Regulated Cytoskeleton-Associated Protein Controls AMPAR Endocytosis through a Direct Interaction with Clathrin-Adaptor Protein 2.''; eNeuro, 2016 PubMed Europe PMC Scholia
  52. Kawaguchi K, Morita M; ''ABC Transporter Subfamily D: Distinct Differences in Behavior between ABCD1-3 and ABCD4 in Subcellular Localization, Function, and Human Disease.''; Biomed Res Int, 2016 PubMed Europe PMC Scholia
  53. Z G Goldsmith, D N Dhanasekaran; ''G Protein regulation of MAPK networks''; Nature, 2007 PubMed Europe PMC Scholia
  54. Resh MD; ''Fyn, a Src family tyrosine kinase.''; Int J Biochem Cell Biol, 1998 PubMed Europe PMC Scholia
  55. Song MS, Rossi JJ; ''Molecular mechanisms of Dicer: endonuclease and enzymatic activity.''; Biochem J, 2017 PubMed Europe PMC Scholia
  56. Kong, Sek Won, Mustafa Sahin, Christin D. Collins, Mary H. Wertz, Malcolm G. Campbell, Jarrett D. Leech, Dilja Krueger, Mark F. Bear, Louis M. Kunkel, Isaac S. Kohane.; ''Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis''; https://doi.org/10.1186/2040-2392-5-16, 2014 DOI Scholia
  57. Westmark CJ, Sokol DK, Maloney B, Lahiri DK; ''Novel roles of amyloid-beta precursor protein metabolites in fragile X syndrome and autism.''; Mol Psychiatry, 2016 PubMed Europe PMC Scholia
  58. Hennig A, Markwart R, Esparza-Franco MA, Ladds G, Rubio I; ''Ras activation revisited: role of GEF and GAP systems.''; Biol Chem, 2015 PubMed Europe PMC Scholia
  59. Porter K, Komiyama NH, Vitalis T, Kind PC, Grant SG; ''Differential expression of two NMDA receptor interacting proteins, PSD-95 and SynGAP during mouse development.''; Eur J Neurosci, 2005 PubMed Europe PMC Scholia
  60. Westmark CJ; ''FMRP: a triple threat to PSD-95.''; Front Cell Neurosci, 2013 PubMed Europe PMC Scholia
  61. Leboucher A, Pisani DF, Martinez-Gili L, Chilloux J, Bermudez-Martin P, Van Dijck A, Ganief T, Macek B, Becker JAJ, Le Merrer J, Kooy RF, Amri EZ, Khandjian EW, Dumas ME, Davidovic L; ''The translational regulator FMRP controls lipid and glucose metabolism in mice and humans.''; Mol Metab, 2019 PubMed Europe PMC Scholia
  62. Kang SJ, Kaang BK; ''Metabotropic glutamate receptor dependent long-term depression in the cortex.''; Korean J Physiol Pharmacol, 2016 PubMed Europe PMC Scholia
  63. Gingras AC, Kennedy SG, O'Leary MA, Sonenberg N, Hay N; ''4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway.''; Genes Dev, 1998 PubMed Europe PMC Scholia
  64. Michael R. Santoro, Steven M. Bray, Stephen T. Warren; ''Molecular Mechanisms of Fragile X Syndrome: A Twenty-Year Perspective''; Google Scholar, 2012 PubMed Europe PMC Scholia
  65. Hayashi MK, Tang C, Verpelli C, Narayanan R, Stearns MH, Xu RM, Li H, Sala C, Hayashi Y; ''The postsynaptic density proteins Homer and Shank form a polymeric network structure.''; Cell, 2009 PubMed Europe PMC Scholia
  66. Hayashi MK, Tang C, Verpelli C, Narayanan R, Stearns MH, Xu RM, Li H, Sala C, Hayashi Y; ''The postsynaptic density proteins Homer and Shank form a polymericnetwork structure.''; Cell, 2009 PubMed Europe PMC Scholia
  67. Huber KM, Klann E, Costa-Mattioli M, Zukin RS; ''Dysregulation of Mammalian Target of Rapamycin Signaling in Mouse Models of Autism.''; J Neurosci, 2015 PubMed Europe PMC Scholia
  68. Goebel-Goody SM, Wilson-Wallis ED, Royston S, Tagliatela SM, Naegele JR, Lombroso PJ; ''Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.''; Genes Brain Behav, 2012 PubMed Europe PMC Scholia
  69. Yang T, Zhao H, Lu C, Li X, Xie Y, Fu H, Xu H; ''Synaptic Plasticity, a Prominent Contributor to the Anxiety in Fragile X Syndrome.''; Neural Plast, 2016 PubMed Europe PMC Scholia
  70. Yun SH, Trommer BL; ''Fragile X mice: reduced long-term potentiation and N-Methyl-D-Aspartate receptor-mediated neurotransmission in dentate gyrus.''; J Neurosci Res, 2011 PubMed Europe PMC Scholia
  71. Bear MF, Huber KM, Warren ST; ''The mGluR theory of fragile X mental retardation.''; Trends Neurosci, 2004 PubMed Europe PMC Scholia
  72. Hansen Wang; ''Fragile X mental retardation protein: from autism to neurodegenerative disease''; Frontiersin, 2015 PubMed Europe PMC Scholia
  73. Kelley DJ, Davidson RJ, Elliott JL, Lahvis GP, Yin JC, Bhattacharyya A; ''The cyclic AMP cascade is altered in the fragile X nervous system.''; PLoS One, 2007 PubMed Europe PMC Scholia
  74. Henley JM, Wilkinson KA; ''AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging.''; Dialogues Clin Neurosci, 2013 PubMed Europe PMC Scholia
  75. Xu W, Schlüter OM, Steiner P, Czervionke BL, Sabatini B, Malenka RC; ''Molecular dissociation of the role of PSD-95 in regulating synaptic strength and LTD.''; Neuron, 2008 PubMed Europe PMC Scholia
  76. Çaku A, Seidah NG, Lortie A, Gagné N, Perron P, Dubé J, Corbin F; ''New insights of altered lipid profile in Fragile X Syndrome.''; PLoS One, 2017 PubMed Europe PMC Scholia
  77. Borrie SC, Brems H, Legius E, Bagni C; ''Cognitive Dysfunctions in Intellectual Disabilities: The Contributions of the Ras-MAPK and PI3K-AKT-mTOR Pathways.''; Annu Rev Genomics Hum Genet, 2017 PubMed Europe PMC Scholia
  78. Wang H, Fukushima H, Kida S, Zhuo M; ''Ca2+/calmodulin-dependent protein kinase IV links group I metabotropic glutamate receptors to fragile X mental retardation protein in cingulate cortex.''; J Biol Chem, 2009 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
134295view05:59, 20 July 2024EgonwRemoved a template comment
127643view19:49, 13 November 2023Khanspersremoved one final it ref for protein database
127642view19:44, 13 November 2023Khanspersremoved literature references to protein/gene databases
127609view14:38, 7 November 2023LarsgwRemove tab character from bp:DB
125304view17:46, 31 January 2023LarsgwFix PMID in reference
124287view13:32, 9 October 2022EgonwModern Uniprot data source
124286view10:37, 9 October 2022VanessaSousa
124285view10:34, 9 October 2022VanessaSousa
123421view06:15, 26 July 2022EgonwMade two pathways clickable
119333view08:04, 24 June 2021FinterlyFixed Biopax PublicationXrefs with missing ID, and removed duplicates
118442view14:46, 27 May 2021Mkutmonfix publication refs
117111view21:38, 17 May 2021EweitzModified title
108088view11:54, 28 November 2019FehrhartOntology Term : 'disease pathway' added !
104796view08:08, 18 June 2019FehrhartConnected unconnected lines
104314view12:15, 16 May 2019MkassChanged direction of arrows from Kras-GTP to Kras-GDP (they were pointed at the wrong direction)
104286view12:39, 15 May 2019FehrhartOntology Term : 'autism spectrum disorder' added !
104285view12:38, 15 May 2019FehrhartOntology Term : 'brain disease pathway' added !
104284view12:37, 15 May 2019FehrhartOntology Term : 'neuron' added !
104037view18:35, 25 April 2019MkassChanged mim conversion arrows from FMR1 to phosphorylated FMR1 because they pointed at the wrong direction
103984view12:12, 23 April 2019MkassChanged location of 'mGluR-LTP --> Amygdala'
103983view09:39, 23 April 2019MkassAddition of MIM inhibition from stalled polyribosomes to target mRNA
103982view09:15, 23 April 2019MkassAdded MIM stimulation (in blue) from FMR1 to GABA mRNAs
103972view12:21, 18 April 2019MkassAdded grey backgroud to AMPAR
103971view12:17, 18 April 2019MkassAdded some annotations on how NMDAR, TrkB and cAMP are affected in FXS
103970view11:16, 18 April 2019MkassRestructuring of the pathway to have a better overview
103892view12:48, 14 April 2019Mkass
103823view13:35, 9 April 2019Mkassupdated legend
103822view13:30, 9 April 2019Mkass
103817view09:57, 9 April 2019Mkass
103814view09:09, 9 April 2019MkassFixed unconnected interactions
103804view19:04, 8 April 2019MkassModified description
103803view18:36, 8 April 2019MkassModified description
103802view18:32, 8 April 2019Mkass
103780view18:11, 5 April 2019Mkass
103776view15:01, 5 April 2019Mkass
103775view10:52, 5 April 2019Mkass
103774view09:23, 5 April 2019Mkass
103773view08:17, 5 April 2019Mkass
103772view07:54, 5 April 2019EgonwFixed a Pubmed identifier.
103762view09:49, 4 April 2019Mkass
103735view13:38, 2 April 2019Mkass
103734view10:15, 1 April 2019Mkass
103733view10:04, 1 April 2019Mkass
103732view09:12, 1 April 2019Mkass
103731view21:11, 31 March 2019Mkass
103730view20:40, 31 March 2019AndraOntology Term : 'fragile X syndrome' added !
103726view10:56, 31 March 2019Mkass
103685view12:39, 28 March 2019Mkass
103684view12:27, 28 March 2019Mkass
103683view11:20, 28 March 2019Mkass

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABATRnaENSG00000183044 (Ensembl)
ABCD3GeneProductENSG00000117528 (Ensembl) ABCD3, a peroxisomal membrane protein, is involved in the transport of branched chain acyl-CoA into peroxisomes. ABCD3 is a fatty acid (FA) transporter protein.
AGAP2GeneProductENSG00000135439 (Ensembl)
AGO2GeneProductENSG00000123908 (Ensembl)
AKAP5GeneProductENSG00000179841 (Ensembl) A-kinase anchor protein 5 (AKAP5) anchors protein kinase A (PKA) at the PSD by directly interacting with PSD-95. This interaction is important for NMDAR-dependant AMPAR endocytosis and LTD.
AKT1GeneProductENSG00000142208 (Ensembl)
AKT1S1GeneProductENSG00000204673 (Ensembl)
ALDH3A2GeneProductENSG00000072210 (Ensembl) Fatty aldehyde dehydrogenase (ALDH3A2) catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acids. ALDH3A2 has shown to be essential for the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation.
ALDH5A1RnaENSG00000112294 (Ensembl)
AP2A1GeneProductENSG00000196961 (Ensembl)
AP2B1GeneProductENSG00000006125 (Ensembl)
AP2M1GeneProductENSG00000161203 (Ensembl)
AP2S1GeneProductENSG00000042753 (Ensembl)
APPGeneProductENSG00000142192 (Ensembl)
  • Amyloid-beta precursor protein (APP), large membrane-spanning glycoprotein, is implicated in neurogenesis and synapse formation. It is mainly expressed in synapses. APP is suspected to contribute to altered mGluR-LTD.
  • Type your comment here
ARAFGeneProductENSG00000078061 (Ensembl)
ARCGeneProductENSG00000198576 (Ensembl) Activity-regulated cytoskeleton-associated protein (ARC) is a key regulator of synaptic plasticity. It is required for protein synthesis-dependent LTP and LTD as well as for the formation of long-term memory. ARC regulates synaptic plasticity by promoting endocytosis of AMPA receptors AMPAR and thus, LTD.
ARHGAP32GeneProductENSG00000134909 (Ensembl) Rho GTPase activating protein 32 (ARHGAP32) is a neuron-associated GAP that may regulate dendritic spine morphology and strength through modulation of Rho GTPase activity.
BDNF-TrkB SignallingPathwayWP3676 (WikiPathways)
BDNFGeneProductENSG00000176697 (Ensembl)
BRAFGeneProductENSG00000157764 (Ensembl)
CAMK1GeneProductENSG00000134072 (Ensembl)
CAMK2AGeneProductENSG00000070808 (Ensembl) calcium/calmodulin dependent protein kinase II alpha (CAMKIIα) is expressed at synapses where its translation is negatively regulated by FMRP. CAMKIIα is a key determinant for AMPAR internalization and thus LTD. The protein kinase mediates AMPAR internalization through phosphorylation of AMPAR subunits. CAMKIIα is involved in synaptic plasticity, neurotransmitter release and LTP.
CAMK2BGeneProductENSG00000058404 (Ensembl) CAMKII catalyzes the phosphorylation of AMPAR an
CAMK4GeneProductENSG00000152495 (Ensembl) CAMK4 or CAMKIV
CAMKIV-CREB PathwayPathway
CDKN2AGeneProductENSG00000147889 (Ensembl) Cyclin-dependent kinase inhibitor 2A (CDKC2A)
CLTAGeneProductENSG00000122705 (Ensembl)
CLTBGeneProductENSG00000175416 (Ensembl)
CLTCGeneProductENSG00000141367 (Ensembl) Clathrin mediates the endocytosis of NMDAR by binding to AP-2
CLTCL1GeneProductENSG00000070371 (Ensembl)
CNR1GeneProductENSG00000118432 (Ensembl)
CPT1AGeneProductENSG00000110090 (Ensembl) CPT1A encodes the hepatic enzyme carnitine palmitoyltransferase 1A. The enzyme is responsible for fatty acid oxidation within the mitochondria, it connects carnitine to long-chain fatty acids thereby enabling the crossing of the fatty acid into the inner membrane of mitochondria. FMRP negatively regulates CPT1A and thus lipid metabolism.
CREB1GeneProductENSG00000118260 (Ensembl)
CYFIP1GeneProductENSG00000273749 (Ensembl) CYFIP1 interacts with FMRP and with translation initiation factor eIF4E
CYFIP2RnaENSG00000055163 (Ensembl)
DAG1GeneProductENSG00000173402 (Ensembl)
DEPTORGeneProductENSG00000155792 (Ensembl)
DICER1GeneProductENSG00000100697 (Ensembl) DICER, is an endonuclease, which cleaves double stranded RNA (dsRNA) into short single stranded RNA called miRNA and tehreby faciliates the activation of RISC
DLG4RnaENSG00000132535 (Ensembl)
DLGAP3GeneProductENSG00000116544 (Ensembl) SAP90/PSD-95-associated protein 3 (SAPAP3) plays a role in the organization of synapses and neuronal cell signaling and is negatively regulated by FMRP. SAPAP3 is a postsynaptic scaffolding protein which is associated with PSD-95 and localized in dendrites. SAPAP3 plays an improtant role in maturation of synapses
DNM2GeneProductENSG00000079805 (Ensembl) Dynamin is a large GTPase modulating release of endosomes from the membrane by pinching off and fissioning the membrane.
DUSP3GeneProductENSG00000108861 (Ensembl) Also referred to as VHR, a ERK specific phosphatase
Dynamin-1ProteinA0A0D9SFB1 (Uniprot-TrEMBL)
EEF1A1GeneProductENSG00000156508 (Ensembl) Eukarytic translation elongation factor (EF1α)
EIF4A1GeneProductENSG00000161960 (Ensembl)
EIF4EBP2GeneProductENSG00000148730 (Ensembl) Phosphorylated 4E-BP cannot bind to eIF4E anymore, this means that its inhibitory effect on translation is repressed
EIF4EGeneProductENSG00000151247 (Ensembl)
EIF4G1GeneProductENSG00000114867 (Ensembl)
EPHA4GeneProductENSG00000116106 (Ensembl) Ephrin type-A receptor 4 (EPHA4) is a receptor tyrosine kinase binding tp ephrin ligands. EPHA4 is has a function in the development of the nervous system.
EPS8L1GeneProductENSG00000131037 (Ensembl) Epidermal growth factor receptor pathway substrate 8-related protein 1 (EPS8L1) is an FMRP target and important for teh remodelling of actin in response to EGF stimulation. EPS8L1 gene product EPS8 is needed for normal spine morphology, synaptic plasticity, and memory formation. EPS8 has been shown to be downregulated in autism, since it's a binding partner of FMRP, it is likely that it is also downregulated in FXS.
FMR1GeneProductENSG00000102081 (Ensembl)
FYNGeneProductENSG00000010810 (Ensembl) Tyrosine-protein kinase Fyn (FYN) is a member of the Src family of tyrosine kinases which is involved in the regulation of brain function.
GAB1GeneProductENSG00000109458 (Ensembl)
GABRA1RnaENSG00000022355 (Ensembl)
GABRB2RnaENSG00000145864 (Ensembl)
GABRDProteinENSG00000187730 (Ensembl)
GABRG2RnaENSG00000113327 (Ensembl)
GAD1GeneProductENSG00000128683 (Ensembl) Glutamate decarboxylase 1 (GAD1) encoded an enzyme (glutamic acid decarboxylase) that has a role in γ-aminobutyric acid (GABA) synthesis. The enzyme catalyzes the production of GABA from L-glutamic acid.
GPHNRnaENSG00000171723 (Ensembl)
GRB2GeneProductENSG00000177885 (Ensembl)
GRIA1GeneProductENSG00000155511 (Ensembl) AMPAR subunit GuA1
GRIA2GeneProductENSG00000120251 (Ensembl) AMPAR subunit GluA2
GRIN1GeneProductENSG00000176884 (Ensembl)
GRIN2AGeneProductENSG00000183454 (Ensembl) NMDA receptor subunit 2 A
GRIN2BGeneProductENSG00000273079 (Ensembl) N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDAR) are ionotropic receptors activated by glutamate. NMDAR activation allows Ca2+ influx leading to NMDAR-dependant LTP and LTD
GRIP1GeneProductENSG00000155974 (Ensembl)
GRIP2GeneProductENSG00000144596 (Ensembl) Glutamate receptor-interacting protein 2 (GRIP2) also called AMPAR binding protein (ABP) interacts with GRIP1 to regulate AMPAR trafficking
GRM1GeneProductENSG00000152822 (Ensembl)
GRM5RnaENSG00000168959 (Ensembl)
HCN1GeneProductENSG00000164588 (Ensembl) Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1)
HOMER1GeneProductENSG00000152413 (Ensembl) Long homer variant
HOXB8GeneProductENSG00000120068 (Ensembl)
ITPR1GeneProductENSG00000150995 (Ensembl)
KCNC1GeneProductENSG00000129159 (Ensembl)
KCND2GeneProductENSG00000184408 (Ensembl)
KRASGeneProductENSG00000133703 (Ensembl)
MAP1BGeneProductENSG00000131711 (Ensembl) Microtubule-associated protein 1B (MAP1B) is involved in mcirotubule assembly and neurogenesis. MAP1b is involved in the regulation of the morphology of dendritic spines in glutamatergic synapses. Furthermore, MAP1b is a negative regulator of AMPAR surface expression thereby contributing to mGluR-LTD.
MAP2K1GeneProductENSG00000169032 (Ensembl)
MAP2K2GeneProductENSG00000126934 (Ensembl)
MAPK1GeneProductENSG00000100030 (Ensembl)
MECP2GeneProductENSG00000169057 (Ensembl) Methyl-CpG-binding protein 2 (MECP2) is a nuclear protein that is capable of binding to methylated DNA. It is essential for nerve cell functionality.
MEK-ERK-Mnk1 PathwayPathwaymap04010 (KEGG Pathway) Activation of ERK pathway is required for mGlur-LTD. ERK activation is thought to control the activation of specific mRNAs such as the LTD proteins.
MKNK1GeneProductENSG00000079277 (Ensembl)
MLST8GeneProductENSG00000167965 (Ensembl)
MMP9GeneProductENSG00000100985 (Ensembl)
MTORGeneProductENSG00000198793 (Ensembl)
NF1GeneProductENSG00000196712 (Ensembl) NF1 functions as a guanine exchange factors (GEF), stimulating the conversion of GTP-bound RAS into GDP-bound RAS and tehreby negatively regulating the MEK-ERK-Mnk1 pathway.
NTRK2GeneProductENSG00000148053 (Ensembl)
PDK1GeneProductENSG00000152256 (Ensembl)
PI3K-Akt-mTOR

Pathway

PathwayWP4172 (WikiPathways) Activation of mTOR pathway is required for mGlur-LTD. mTOR activation is believed to sustain the increase in overall rate of mRNA translation at the synapse.
PICK1GeneProductENSG00000100151 (Ensembl) Protein Interacting with Kinase C 1 (PICK1)
PIK3CBGeneProductENSG00000051382 (Ensembl)
PIP2MetaboliteCHEBI:18348 (ChEBI)
PIP3MetaboliteCHEBI:16618 (ChEBI)
PLCB1GeneProductENSG00000182621 (Ensembl)
PLCG1GeneProductENSG00000124181 (Ensembl)
PPP1CAGeneProductENSG00000172531 (Ensembl) PP1 had 4 isomforms, however, in this pathway, only one (gene PPP1CA) has been used since literature did not specify which isoform is involved in this specific case.
PPP2R5BGeneProductENSG00000068971 (Ensembl)
PPP3CAGeneProductENSG00000138814 (Ensembl) Calcineurin
PRKACAGeneProductENSG00000072062 (Ensembl)
PRKAR1AGeneProductENSG00000108946 (Ensembl)
PRKCAGeneProductENSG00000154229 (Ensembl)
  • Protein Kinase C
  • mGluR activation leads to activation of the PLC pathway which induces release of Ca2+ and PKC. PKC will phohsphorylate and activate RAF1 and tehereby activate RAF1 and thus the ERK pathway
PTENRnaENSG00000171862 (Ensembl) PTEN is enhanced by FMRP and negatively regulates GABA A receptor subunits, this way PTEN has a protective role in reducing GABA A deficiency-indiced incidence of seizures
PTPN11GeneProductENSG00000179295 (Ensembl)
PTPN5GeneProductENSG00000110786 (Ensembl) Tyrosine-protein phosphatase non-receptor type 5 (STEP) is involves to regulate AMPAR trafficking and negatively regulates AMPAR surface expression thereby contributing to mGluR-LTD. STEP promotes LTD by stimulating synaptic weakening by dephosphorylation of ERK1/2 and subunits of NDMA and AMPA receptors. STEP has been shown to promote NMDA internalization.
RAF1GeneProductENSG00000132155 (Ensembl)
RAP1GAPGeneProductENSG00000076864 (Ensembl) RAP1 is phsohprylated and activated by PKA and in turn stimulates the activation of B-Raf, thus leading to the activation of the ERK pathway
RHEBGeneProductENSG00000106615 (Ensembl)
RPS6KB1GeneProductENSG00000108443 (Ensembl)
RPTORGeneProductENSG00000141564 (Ensembl)
SH3GL1GeneProductENSG00000141985 (Ensembl) Endophoilin 2
SH3GL3GeneProductENSG00000140600 (Ensembl) Endopilin 3
SHANK1GeneProductENSG00000161681 (Ensembl) Shank, an adapter protein in the PSD of excitatory synapses, is necessary for the structural and functional integrity of dendritic spines and synaptic junction.
SHC1GeneProductENSG00000160691 (Ensembl)
SLC16A1GeneProductENSG00000155380 (Ensembl) Monocarboxylate transporter 1 (MCT1) is a proton coupled monocarboxylate transporter which function is to catalyse the rapid transport of many monocarboxylates across the plasma membrane.
SLC6A1RnaENSG00000157103 (Ensembl)
SOS1GeneProductENSG00000115904 (Ensembl) SOS, a guanine-associated echange factor (GEF), activates Ras by inducing the exchange of GTDP by GTP. This positively regulates Ras signalling.
SRCGeneProductENSG00000197122 (Ensembl)
SYNGAP1GeneProductENSG00000197283 (Ensembl)
TARBP2GeneProductENSG00000139546 (Ensembl)
TBC1D7GeneProductENSG00000145979 (Ensembl)
TECRGeneProductENSG00000099797 (Ensembl) Very-long-chain enoyl-CoA reductase (TECR) is responsible to catalyze the last of the four reactions of the long-chain fatty acids elongation cycle.
TELO2GeneProductENSG00000100726 (Ensembl)
TSC1GeneProductENSG00000165699 (Ensembl)
TSC2GeneProductENSG00000103197 (Ensembl)
TTI1GeneProductENSG00000101407 (Ensembl)
cAMPMetaboliteCHEBI:17489 (ChEBI)
endocannabinoidsMetaboliteCHEBI:67197 (ChEBI)
glutamateMetaboliteCHEBI:14321 (ChEBI)
miR-125b RnaMIMAT0042091 (miRBase mature sequence)
miR-132 RnaMIMAT0004594 (miRBase mature sequence)
miR-196a RnaMIMAT0000226 (miRBase mature sequence)
γ-aminobutyric acidMetaboliteCHEBI:16865 (ChEBI) γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system.

Annotated Interactions

No annotated interactions

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP4549"
Personal tools