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Lee BE, Kim HY, Kim HJ, Jeong H, Kim BG, Lee HE, Lee J, Kim HB, Lee SE, Yang YR, Yi EC, Hanover JA, Myung K, Suh PG, Kwon T, Kim JI. O-GlcNAcylation regulates dopamine neuron function, survival and degeneration in Parkinson disease. Brain : a journal of neurology 2020 143(12) 33300544
Abstract:
The dopamine system in the midbrain is essential for volitional movement, action selection, and reward-related learning. Despite its versatile roles, it contains only a small set of neurons in the brainstem. These dopamine neurons are especially susceptible to Parkinson's disease and prematurely degenerate in the course of disease progression, while the discovery of new therapeutic interventions has been disappointingly unsuccessful. Here, we show that O-GlcNAcylation, an essential post-translational modification in various types of cells, is critical for the physiological function and survival of dopamine neurons. Bidirectional modulation of O-GlcNAcylation importantly regulates dopamine neurons at the molecular, synaptic, cellular, and behavioural levels. Remarkably, genetic and pharmacological upregulation of O-GlcNAcylation mitigates neurodegeneration, synaptic impairments, and motor deficits in an animal model of Parkinson's disease. These findings provide insights into the functional importance of O-GlcNAcylation in the dopamine system, which may be utilized to protect dopamine neurons against Parkinson's disease pathology.
O-GlcNAc proteins:
BIG2, F1712, VIR, AJM1, RPGP1, UBR4, SCN1A, AGRIN, TITIN, KALRN, STPG3, FXL16, TT23L, PTPRS, GRIK3, SCN2A, DLGP4, OSBL8, PTPRZ, PGBD5, GLSK, GCN1, CE350, PI4KA, RYR2, AGRF2, UBE4A, NRX2A, FRY, SYGP1, OTOGL, AT2B1, ANK3, CA2D1, DPYL2, STXB1, DCTN1, U5S1, GFRA2, GALT1, SEM4D, KIF3C, PLCA, PHB2, NCAM2, GRAK, PURB, IMA3, IMA7, PLD3, FOLH1, FKBP8, STX1A, PSDE, VIAAT, AP1B1, C1QBP, SYT3, HNRH1, SATT, CTND2, SDC4, AP3D1, RGS9, RGS7, CSK22, OX2G, AAKG1, CRYM, PROM1, CNTP1, ENTP2, BCKD, SNG1, NIPS1, NIPS2, SEPT7, AT2A2, DHX9, PI51C, PI42A, ITB5, GPX4, NPTX2, GNAZ, WDR1, S4A4, MTX2, CNTFR, ZFR, CSN3, HCN2, HCN1, CTBP1, BSN, MPP3, NOE1, CBPD, LGMN, COR1A, CYB, COX1, COX2, COX3, HPRT, ATP6, THY1, H3C, LAMC1, NU1M, NU2M, NU4M, NU5M, ATP8, GFAP, MBP, PRIO, ALDOA, KAPCA, AATM, TBA1B, TBA3, KIT, LDHA, G6PI, MDR1B, ENPP1, HS90A, ENPL, KCC4, NFL, NFM, RASN, PGK2, ITB1, PPBT, NUCL, PGK1, ACE, LRC4B, UBB, UBC, EF1A1, IF4A2, GSTM1, 4F2, H10, LAMP1, HS90B, L1CAM, ITA5, KCC2A, ITB2, ITPR1, TCPA, PFKAL, CNTN1, NCAM1, AT1B1, C1QB, RS16, RL7, AT1B2, PSMD3, MAP1B, GLNA, CADH2, INSR, NTRK2, KCNC1, SPTB1, H12, KPCE, LDHB, CN37, DDX3L, KCNA1, KCNA3, AMPE, ASSY, SPTN1, G3P, LAMP2, ENOA, AP2A1, AP2A2, HXK1, GTR1, PTPRA, COF1, GNAO, FAS, LAMA1, NFH, COX41, BIP, HEXB, VIME, MTAP2, MAG, GNA11, GNAQ, MDR1A, ACES, GBRG2, AP1G1, GBRD, EIF3A, CXA1, GRIA1, GRIA2, TY3H, RS2, GBRA2, RL3, BRAF, KCC2B, NP1L1, NCKP1, SNAB, KIF2A, KIF3A, PABP1, GBB4, KCRU, GNA14, KAP3, SC6A1, S6A11, MP2K1, GTR3, LA, RASK, SYWC, KIF1A, HYES, RAB3D, RAB5C, RAB6A, RAB21, NMDZ1, ODPA, RET, FBRL, KCNJ2, CD81, GPM6A, GPM6B, GNL1, DYN1, DYN2, GRIK2, CAP1, ABCA2, PURA, HD, EAA2, H14, H15, H13, ITAV, SYT1, NSF, RB11B, AINX, MYO1B, NEDD4, ALDH2, GRM8, CAZA2, CAPZB, MP2K4, PFKAM, RL6, RL29, RL5, GLRB, DCE1, DCE2, CBR1, GSTM5, ADT1, INPP, CDK5, SAHH, GDIA, VATA, VATE1, GBRB1, RAB7A, ACADL, VA0D1, ADT2, EAA3, KCNJ4, KPYM, RAB2A, PRS6B, PTN5, NCAN, ABCD3, RAB8A, ATPK, ATP5E, UBP5, ATPB, CTBP2, EAA1, WFS1, FUS, NICA, ACTN4, ASM3B, EF2, OPA1, DOCK4, IRPL1, ARPC4, MYPR, PLPP, ACTB, MDGA2, NEUG, RAC3, IF4A1, MEGF8, RAB5B, RAB10, RAB8B, ARP2, ACTZ, CSN2, ARF3, ARL1, CAH10, RAP2B, STX1B, RAB6B, RL27, ARF4, GABT, HNRPK, 1433G, RS7, PP1A, RS8, SMD1, KCAB2, ABI2, RB11A, EF1A2, RS4X, PP2AB, RL18A, ACTA, AP2S1, RL23A, VISL1, H4, GBRA1, VATB2, RAB1A, RAB3C, RAN, RAP1A, RS24, GBB1, GBB2, RS3, RL8, RS27A, RL40, RAC1, RAB3A, HSP7C, CH60, VAMP2, NOE3, GBRB3, VATL, PP1G, 1433Z, GBRB2, KCNA2, KCAB1, CRNL1, DYL1, ACTG, ACTH, KPCG, PP2BA, PP2AA, PHB, CSK2B, ACTC, RACK1, ACTS, KAPCB, TBA4A, TBA1A, TBB4B, KPCB, H31, IMB1, PLXA1, PLXA2, PLXA3, DCC, ITPR3, NCHL1, HNRH2, ELAV1, USP9X, IDHG1, LYAG, AT8A1, TCPH, TCPB, TCPD, TCPE, TCPZ, TCPG, TNIK, WNK1, RL36A, ARF1, ARF5, AP2M1, H32, H33, ADCY5, NPTN, RS3A, AT1B3, DPYL1, ZNT3, GRM1, SHPS1, NEO1, FUMH, M4K4, C1QA, TBB5, PDE4D, PDE1B, NMDE2, SC23A, TERA, C1QC, CTNB1, PLAK, EPHA4, MARK3, ATPA, CHLE, KCND1, KCRB, NF1, CDK18, RAC2, MARK2, PGBM, PTPRG, PYC, KCMA1, PADI2, INF2, TRIO, MDGA1, CTP5A, ITB8, PSA, GRM2, PTCD3, PHAR1, LRFN1, SPP2B, HP1B3, NLRX1, PRC2C, TM38A, VGLU1, BIG3, PLXD1, AGAP2, AAK1, TEN4, CAMKV, DOP2, RMD3, SMU1, MCCB, GPD1L, LIGO2, SRBS2, CDKL5, K22O, VPS51, GRM5, CBAR2, SHAN3, UN13A, SE6L2, KCTD8, KCD16, LRC8B, VP13A, C2C4C, S2551, MRS2, DIRA2, CYFP2, TM1L2, RHG44, MYO1D, RABL6, DJC11, UIMC1, ICAM5, FLOT2, HNRPD, PTPRN, CSK21, KHDR1, IGF1R, CLD11, SPB6, ARHG2, VDAC2, VDAC3, VDAC1, ABCB7, ASTN1, P3C2A, CAC1E, LAMB2, CTNA2, SC6A3, CNTN2, PGCB, NEP, KCNA4, CD166, 5NTD, GSLG1, EWS, AP180, FSCN1, GDIB, GRIK5, GRID1, DDX5, HS105, ITIH3, IL1AP, CD47, KINH, KIF3B, LASP1, MYH10, MOG, NPM, PCBP2, CSPG2, DDX3Y, DLG4, RHOC, DAG1, DDX3X, SYPH, TICN1, NDUA4, NPTX1, NUP62, OMGP, HECAM, AOFA, ARP3B, SURF4, SYN2, CP3AD, H2B1H, GLPK, SDC3, GPDM, H2A2C, H2B2B, GRM7, GRM4, CLH1, K1549, GIT1, PKP4, PPR29, CNTN4, NLGN2, SV2C, THS7A, CE170, UBP7, BRNP2, SCMC3, LIGO3, DGKB, RPRD2, DPP10, S23IP, PPRC1, 2ABA, TNPO3, SIK3, U520, S39AA, TTYH3, XPO1, SPCS, KCRS, CSKI1, NRX3A, BCR, SARM1, PRRT3, TEFF1, RAB35, CA2D2, KCC2D, AT1A3, AT1A2, GNAS1, SDK2, WDFY3, NTRK3, RAD9B, DGLA, KCD12, MTMR5, UBE2O, CAND1, UBP34, RS9, 2ABB, H2B1C, TLN2, CSPG5, 2AAA, NP1L4, MTCH2, OPALI, CYFP1, TBB2A, HUWE1, IGS21, ROBO2, ACTN1, IGSF1, TR143, TPPP, OTUB1, KPBB, PP6R1, MAP6, ELP1, RRAGD, MRCKB, GABR2, CSMD3, EPT1, VAT1L, LRRC7, CAPS1, CYLD, AGRL1, AGRL3, CLAP1, AUXI, DAAM2, MADD, MFN2, NU214, UBE3C, PLXA4, FBX2, KCMF1, CBPM, GSTM7, AGFG2, LRC8A, HPLN4, VAC14, UBP2L, C2C2L, LRRT4, BDH, MK15, CNKR2, TENA, ASTN2, NEGR1, RAP2A, THEM6, SLIK5, SLIK4, SLIK3, SLIK2, NFASC, NRCAM, RHG32, SRGP3, EFTU, VGLU3, ERLN2, ROA3, SV2B, MIRO1, EFR3A, LRRT2, U2AF4, ENPP6, SYAC, FLRT3, CBLN2, LRTM2, HPCL4, COR2B, CMC1, ATLA1, NU107, RB39B, RB39A, ZN526, ANS1B, DLGP2, AHSA1, IPO5, NCEH1, LSAMP, CADM2, NOE2, ODP2, RBGPR, ECHA, SPA2L, SYNC, RL24, DAAM1, DMXL2, RLGPB, CLAP2, VMAT2, ARF2, NDRG4, ENPP4, HSDL1, RAP2C, GEPH, VATH, PMGT2, TTC12, AOFB, LRFN5, PIGT, CTL2, TENR, NLGN3, LRRT3, DYN3, LRC4C, ARHGA, SYFA, SI1L1, LCAP, EXOG, CERS6, SEP11, IKZF4, GP158, CWC22, VPS52, SCAI, ANK2, PDE10, PGM2L, SHFL, MIC60, WDR37, ABI1, SYNPO, T132C, GLT13, NED4L, RPB2, TCRG1, GNAL, H2B1K, H2B1P, H2A1F, H2A1H, H2A1K, OGT1, SYNJ1, SEPT8, MBOA7, PGP, NGEF, PYGB, COPA, MARK4, DOCK3, PLXB1, TXTP, AGRL2, TRHDE, R4RL1, RTN1, HS12A, K319L, DNM1L, AGRG1, PACS1, ABCF3, SDHA, HACD3, AGFG1, PAF1, IPO11, CCM2, MATR3, ATAT, LRRT1, LGI3, RPTOR, COL12, NAC2, THIL, EIF3L, MARE2, HNRPL, K0513, IQEC1, CACB4, SCPDL, BPHL, SNG3, EIF3C, H2AJ, DC1L1, S35A3, AP3M2, MUC18, UBQL1, PSPC1, NUP58, IGSF8, EXOC1, CACB1, CADM4, NUP85, SNP47, ACTY, WASF1, AMPB, MICU1, PSMD2, AT1A1, CDIPT, GD1L1, CC50A, HNRPU, REM2, MPCP, MARK1, CSPG4, SORC3, IPO4, SFPQ, BACH, S12A5, RAB14, SFXN3, ACLY, NDUS1, ITM2C, RMXL1, MIC25, ATPG, DDX1, MLP3A, UBAP2, ACSL6, NDUS2, ERLN1, DLG2, PI42C, IPO9, NDUV1, GRHPR, SRGP2, SRGP1, RAB4B, LRP1, WDR7, BRNP1, SYDC, TBB6, PDK3, TSN2, PDE2A, RPAB3, CSMD1, KCC2G, 2ABD, ATAD3, SFXN5, MYO5A, G37L1, RAP1B, SFXN1, NLGN1, NONO, RRAGC, TIP, MLF2, GAK, CDS2, NDUAA, ETFA, TNPO2, PTPRT, DNJA3, T121B, SF3B1, RIMS1, CNTP4, NTRI, PRP8, COX6C, MGST3, CNTP2, 6PGL, QCR8, NDUB4, RAB5A, GLRX3, AT5F1, S2546, MLP3B, 1433B, RL14, M2OM, UCRI, MIC19, PRPS2, NRX1A, MICU3, ARPC2, TBB2B, ROA0, CENPV, RL11, ILF2, TECR, RN181, BIEA, QCR1, OLA1, RL15, AL1B1, TOM70, MPC2, ODPB, MMS19, MGRN1, HNRPM, SCOT1, DYL2, RM28, RAB1B, LIGO1, RUFY3, MEII1, ATAD1, CUL5, GBRA4, TBB4A, GHC1, IDH3A, PRPS1, U2AF1, RL4, PSD12, SNAA, ATPO, BTBDH, QCR2, ALG2, AP2B1, RPN2, SUSD2, NDUA9, NDUS7, 6PGD, EIF3F, NDUS3, RAB13, XPO7, IPO7, NBEA, SORC2, VPS35, RPGF4, TBB3, XPO2, RTN3, LRBA, SPN90, TRIM2, DYHC1, LRP1B, LGI1, PRAF2, SV2A, SCAM5, NECT1, HYOU1, EXTL1, SORC1, DCLK1, MTOR, MINK1, ZN207, AP3B2, MY18A, RHOA, HPLN1, FAK2, NAGAB, COPG2, KI21A, SHRM3, PLEC, DREB, CMC2, EHD3, PLXB3, ADDA, DNJA2, GRM3, PCLO, SIA7A, ARP10, DCTN5, PLXC1, COPG1, GPC1, UBQL2, FBX6, SRR, AT2B2, CELR2, DEST, ARC1A, KAD1, GBRG1, GUAD, CBLN1, DGKE, VAS1, ADA22, ADA23, PEPL, CAD13, TEN1, TEN2, CUL1, ATRN, GLPK2, PDC6I, PFKAP, PYGM, SUCA, RBMX, GABR1, GSK3B, FPRP, E41L3, BUB3, CARM1, PSD13, CP46A, APC7, NCDN, ITB6, KCND2, NU160, HNRDL, SAE2, VATC1, VPP1, ARI1, CA2D3, SEPT3, AP3B1, STK39, HNRPC, DPP6, E41L1, SUCB1, SEPT5, GRIA4, GRIA3, HOME1
Species: Mus musculus
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Deracinois B, Camoin L, Lambert M, Boyer JB, Dupont E, Bastide B, Cieniewski-Bernard C. O-GlcNAcylation site mapping by (azide-alkyne) click chemistry and mass spectrometry following intensive fractionation of skeletal muscle cells proteins. Journal of proteomics 2018 186 30016717
Abstract:
The O-linked-N-acetyl-d-glucosaminylation (O-GlcNAcylation) modulates numerous aspects of cellular processes. Akin to phosphorylation, O-GlcNAcylation is highly dynamic, reversible, and responds rapidly to extracellular demand. Despite the absolute necessity to determine post-translational sites to fully understand the role of O-GlcNAcylation, it remains a high challenge for the major reason that unmodified proteins are in excess comparing to the O-GlcNAcylated ones. Based on a click chemistry approach, O-GlcNAcylated proteins were labelled with azido-GalNAc and coupled to agarose beads. The proteome extracted from C2C12 myotubes was submitted to an intensive fractionation prior to azide-alkyne click chemistry. This combination of fractionation and click chemistry is a powerful methodology to map O-GlcNAc sites; indeed, 342 proteins were identified through the identification of 620 peptides containing one or more O-GlcNAc sites. We localized O-GlcNAc sites on proteins involved in signalling pathways or in protein modification, as well as structural proteins. Considering the recent role of O-GlcNAcylation in the modulation of sarcomere morphometry and interaction between key structural protein, we focused on proteins involved in the cytoarchitecture of skeletal muscle cells. In particular, several O-GlcNAc sites were located into protein-protein interaction domains, suggesting that O-GlcNAcylation could be strongly involved in the organization and reorganization of sarcomere and myofibrils.
O-GlcNAc proteins:
A2A7H5, MYOM3, CKAP5, BRWD3, A2AIR2, DCA10, A2AMY5, B1AXE9, B1AXR5, B1B0C9, B2RXQ9, B7ZC18, B8JJB2, D3YU08, D3YUW7, D3YVS1, D3YYR9, D3Z216, D3Z2W0, D3Z4C0, D3Z589, D3Z6H5, D3Z7Q3, D6RH90, D6RHQ6, E0CYM1, E9Q016, I2BP2, E9Q3W4, KIF23, E9Q616, E9Q6A3, E9Q6Q2, E9Q8K5, E9Q9Q7, E9QKG6, E9QNY8, E9QQ33, F6T0L5, F6UTU1, F6V513, F6WNS2, F6YRR2, F7AWU3, F7C957, F7D291, F8VQK3, F8WGN6, F8WIT2, G3UYW7, G3UZ19, G3X9H7, G3XA78, G5E8J9, H3BK97, CELR1, LNX1, PDLI1, UBB, HSPB1, VIME, CRYAB, CRYAA, TNR6, TLN1, DESM, AIMP1, RAB6A, FOXK1, CNR1, WN10B, LMNA, LIMK1, MRTFB, ACTB, HSP7C, IPKA, ACTC, RGRF2, MYBPH, NACAM, WNK1, STAC, CADH6, G3BP2, G3BP1, NOTC1, ENAH, NF1, INF2, Q3TBU7, MILK2, FOXK2, FCSD2, HERC2, TRI67, TAB3, FBXL7, MYPN, ICEF1, Q5SQY9, TLL1, SRBS1, DBNL, SH3G1, ZYX, M3K10, SH3R1, NCK5L, HYCCI, WDFY3, AKIB1, FHOD3, SI1L2, PKHH1, CYLD, DCAF1, TCPR1, DAPK1, MYPT2, CNOT4, Q8BUJ6, KANK2, IFFO1, ANKK1, VCIP1, CBPC2, TAB1, ASPP2, PDLI5, PP14C, KLH20, MARK1, SYNP2, UBP26, FLIP1, TX1B3, MYPT1, SYNCI, LIMA1, RBP2, LDB3, ADRM1, BAG3, LIMD1, MACF1, Q9Z1A1
Species: Mus musculus
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