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There are many different neurodegenerative diseases which are classified according to the specific proteins involved and the regions of the brain which are affected. Despite individual differences, there are common mechanisms at the sub-cellular level leading to loss of protein homeostasis. The two central systems in protein homeostasis are the chaperone system, which promotes correct protein folding, and the cellular proteolytic system, which degrades misfolded or damaged proteins. Since these systems and their interactions are very complex, we use mathematical modelling to aid understanding of the processes involved. The model developed in this study focuses on the role of Hsp70 (IPR00103) and Hsp90 (IPR001404) chaperones in preventing both protein aggregation and cell death. Simulations were performed under three different conditions: no stress; transient stress due to an increase in reactive oxygen species; and high stress due to sustained increases in reactive oxygen species. The model predicts that protein homeostasis can be maintained during short periods of stress. However, under long periods of stress, the chaperone system becomes overwhelmed and the probability of cell death pathways being activated increases. Simulations were also run in which cell death mediated by the JNK (P45983) and p38 (Q16539) pathways was inhibited. The model predicts that inhibiting either or both of these pathways may delay cell death but does not stop the aggregation process and that eventually cells die due to aggregated protein inhibiting proteasomal function. This problem can be overcome if the sequestration of aggregated protein into inclusion bodies is enhanced. This model predicts responses to reactive oxygen species-mediated stress that are consistent with currently available experimental data. The model can be used to assess specific interventions to reduce cell death due to impaired protein homeostasis.. 7, 6.\n                            Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom. c.j.proctor@ncl.ac.uk"],"submitter_mail":["c.j.proctor@ncl.ac.uk"],"submitter_affiliation":["University of Newcastle"],"publicationId":["BIOMD0000000344"],"pubmed_abstract":["Neurodegeneration is an age-related disorder which is characterised by the accumulation of aggregated protein and neuronal cell death. There are many different neurodegenerative diseases which are classified according to the specific proteins involved and the regions of the brain which are affected. Despite individual differences, there are common mechanisms at the sub-cellular level leading to loss of protein homeostasis. The two central systems in protein homeostasis are the chaperone system, which promotes correct protein folding, and the cellular proteolytic system, which degrades misfolded or damaged proteins. Since these systems and their interactions are very complex, we use mathematical modelling to aid understanding of the processes involved. The model developed in this study focuses on the role of Hsp70 (IPR00103) and Hsp90 (IPR001404) chaperones in preventing both protein aggregation and cell death. Simulations were performed under three different conditions: no stress; transient stress due to an increase in reactive oxygen species; and high stress due to sustained increases in reactive oxygen species. The model predicts that protein homeostasis can be maintained during short periods of stress. However, under long periods of stress, the chaperone system becomes overwhelmed and the probability of cell death pathways being activated increases. Simulations were also run in which cell death mediated by the JNK (P45983) and p38 (Q16539) pathways was inhibited. The model predicts that inhibiting either or both of these pathways may delay cell death but does not stop the aggregation process and that eventually cells die due to aggregated protein inhibiting proteasomal function. This problem can be overcome if the sequestration of aggregated protein into inclusion bodies is enhanced. This model predicts responses to reactive oxygen species-mediated stress that are consistent with currently available experimental data. The model can be used to assess specific interventions to reduce cell death due to impaired protein homeostasis."],"pubmed_title":["Modelling the role of the Hsp70/Hsp90 system in the maintenance of protein homeostasis."],"pubmed_authors":["Proctor Carole J CJ, Lorimer Ian A J IA"],"description_synonyms":["projections, ATHSP70, Hsp86-1, extracellular signal-regulated kinase activity, GrpL, GRPL, pp44mapk, SAPKa, Growth factor receptor-binding protein, Globular Protein Folding, CRKII, l(3)L3929, NURF38, Hsc-4, Neurologic Diseases, scd, beta-tubulin folding, p38-alpha, C81438, p38MAPK, Long Term, p38a, p38ALPHA, Hog, protein polypeptide chains, Donor Artificial Insemination, STOP, LeMPK3, Neurologic Disorders, hnRNP A2/B1, p44mpk, LAP-2, CDA2, Dp38, Pro Oxidant, SAPK1, SAPK2, Mpk34C, JNK-46, hsp4, p38B, irp94, p38A, DmelCG6489, DiE, average, DmelCG18743, hsp70 Ba, Degenerative Condition, mapk14a, DBSK/JNK, pp42, Junk, hrp40, Nonmigrant, HSPH2, HS24/P52, hnRNP36, proteins, inhibition of homeostatic process, suprasegmental levels of nervous system, Hrb87Fa, Dm p38b, Transient, c-ros-1, Hsp70Bc, Hrb85CD, Hsp70Bb, hsp70 Aa, Hsp70Bd, chaperonin-mediated tubulin folding, Oxygen, hrp36, HSPN, h, Degenerative Neurologic Disease, Grf40, Cytoplasmic Inclusions, Role Concepts, dMKK3, Homo sapiens disease, hspn, GRBLG, ESTS:186F5S, hsc70, DmMPK2, Hsp70b, Hsp70a, suprasegmental structures, Hsp84-1, anatomical protrusion, dJNK, 6.3.2.-, csbp, ERK-2, CG4634, Longterm Effect, 89kDa, CG1242, PMK-2, PMK-1, HS24|P52, HSP70Bbb, Hrb87f, PMK-3, partial functionality, Hsp70B, 83K HSP, CSBP, mature diencephalon, Cytoplasmic Inclusion, Hsp70A, Role Concept, Globular Protein, co-chaperonin activity, Double ring-finger protein, Dm-hsp70, git10, shelf, Role, Heterologous Insemination, Cellular, D-MPK2, GRAP-2, Protein Foldings, ARABIDOPSIS HEAT SHOCK PROTEIN 70, Migrants and Transients, DmelCG4264, DmelCG5475, Mek3, MEK3, DMEK3, Degenerative Diseases, Radical, Neurologic Disease, Neurodegenerative disease, c-Crk, projection, ridge, AGE, experimental procedures, hsp-70, NURF-38, CSBP2, Artificial Insemination, DJNK, co-chaperone activity, CSBP1, Globular Protein Foldings, MCF3, 90kDa, Hsp70A7d, dhsp70, Csbp2, Migrants, HSC70-4, Csbp1, CG31449, CG5834, l(3)j7A4, D-p38 MAPK, Grf40 adapter protein, HSP89A, Effects, lamellae, Foldings, Degenerative Neurologic Disorders, hs70, impaired, AL022974, protein-containing complex, GRB-2-like protein, Exip, AID, process of organ, Aid, bs17d06.y1, DOI, 87A, lamella, PRKM15, Prkm8, Stable tubule-only polypeptide, Publication, dMPK2, hsp70RY, PRKM14, p38 MAPK, DMHSP7A2, Gene Products, sapk2a, disease or disorder, Globular, EXIP, dNURF, hsp70Bb-prime, aid, DmelCG5680, doi, ERK, DJNK/bsk, PRKM1, Insemination, p38beta, PRKM2, hsp90a, Hrp36, anatomical systems, JTV1, p38Ka, STOP145, DMHSP7D1, Longterm, BAP74, p38Kb, dysfunction, Hsp 70, JNK21B1|2, AI848995, Long-Term, Worker, PRKM8, CG31359, BC023857, Hsc70, CG31354, GRB2L, Cellular Inclusion, Neurologic, CG12749, Neurologic Degenerative Diseases, HSC70, HEL-S-284, Protein Folding, accidental cell death, Degenerative Neurologic Diseases, negative regulation of homeostatic process, Hsp-70Aa, Spinal Cord, HRP36, Pro-Oxidant, STK26, Hsc4p, p38-2, laminae, myelin basic protein kinase activity, Heterologous, CG31366, SAPK1c, Dp38b, Dp38a, RING finger protein 19A, SAPK2A, 2810411E12Rik, Neurologic Disorder, JNK3alpha1, Proteins, disorders, MAP-2 kinase activity, thalamencephalon, Protein GADS, function, encephalon, Hsp70ab, Cell, Concept, Human Donor, DmMKK3, hsp70A, hsp70B, E(csp)1545, EL52, JNK/SAPK, PDIP38, 86kDa, N-acetyl-D-glucosamine 2-epimerase, native protein, JNK1, Inclusion Body, hsc70-4, p38MAPKK, D-JNK, Long Term Effects, JNK1A2, condition, 145-kDa STOP, Donor, ROS, regulation of homeostatic process, Death, p38 beta, 143198_at, organ process, Artificial, Nurf38, hsp70a, dhsp70Aa, hsp70b, l(3)03550, lap2, Arp2, ARP2, increased number, P42MAPK, i190, Crk1, Neurologic Degenerative Conditions, Crk3, Understanding, CSPB1, Body, Longterm Effects, SAPK1C, Gene Proteins, processes, DmHSP70AA, 38 kDa DNA polymerase delta interaction protein, having decreased function, D-MKK3, CRK1, ORF1, CG5680, Nomads, Pro-Oxidants, Central Nervous System, DmelCG31449, Hsp70Bbc, HSP70Bc, Hsp70aB, Nurf 38, sapk2, hspca, Mpk2, Mpk3, Hsp70, Crko, p42mapk, protein, Neurologic Degenerative Condition, heat shock protein 70, D-p38, E(sev)3A, BSK, Bsk, Crk-II, p38 alpha, NURF, neuron cell death, Neurodegenerative Diseases, DmelCG1242, between brain, dysfunctional, HSP70, stc, APG-2, Readability, DmelCG4634, AL024080, p38/NURF-38, diseases, Roles, Hsp110, Concepts, diseases and disorders, LAP2, synganglion, mitogen-activated protein kinase activity, Q14, Q16, protein aggregate, mpk2, RK, Effect, Donor Artificial, Nervous System Degenerative Diseases, Adapter protein GRID, HSP82, increased, anon-WO0068693, human disease, RY, Migrant Worker, DMKK3, Hsp89, DmelCG5834, hsc4, Hsp84, long, MEK3/MKK3, Hsp86, Hsp90, xhsp70, DmelCG31359, E(sina)2, AI849689, Neurodegenerative Disorder, hspc1, HSPC322, l(3)j5C2, Folding, HSP90, MP kinase activity, 38, GRP78, Dmp38a, AHA1, Hematopoietic cell-associated adapter protein GrpL, Dmp38b, papilla, Neurologic Degenerative Disease, Squatters, DmelCG12749, MBP kinase II activity, homeostasis, c-Jun, P11, DmelCG31366, Hsp82, CG4264, necrosis, CG5475, Long-Term Effects, Neuro-degenerative disease, HSP83, HSP86, HSPCAL1, HSPCAL4, D-junk, MAP kinase 2 activity, Papers, dHsp70, Oxygen Radical, lamina, flanges, ERK1, ERK2, A230093K24Rik, Erk2, Hrb2, D-P38a, GrbX, GRBX, betweenbrain, D-p38b, chaperone activity, shortened, JNK21B1/2, D-p38a, Menstruation, en(lz)3C/4C, p41mapk, positive regulation of homeostatic process, Syn, MAPK, RENBP, Migrant, Progressive neurodegenerative disorder, alpha-tubulin folding, Mtap6, P38, Workers, C14orf3, Oxygen Radicals, HSC4, Hsc4, CG12244, HRB87F/hrp36, non-neoplastic., HSP90N, Inclusion, SH3-SH2-SH3 adapter Mona, figures, GADS, JTV-1, anon-EST:Liang-2.53, Hsp70-BC, Hsp70-Ab, shelves, HRB87F, Mona, p38alpha, common, p38, Prkm15, HSP90A, lacks function of type, Prkm14, low functionality, loss of, Proto-oncogene c-Crk, disease, Degenerative, spine, p41, p40, multichaperone pathway, DmelCG12304, CG6489, short, 186F5S, 83, BSK/DJNK, accessory, the brain, other disease, l(1)G0252, Cellular Inclusions, experimental, Bodies, CG7393, Gene, hsp70(87A), Reactive Oxygen Intermediates, hsp70Ab, hsp70Aa, HEL-S-5a, supernumerary, cerebral degeneration disease, Migrant Workers, interbrain, protrusion, CrkIII, Hsp70-1, p38Hog, dp38a, dp38b, Gads, polypeptide chain, chaperonin ATPase activity, swo1, non-chaperonin molecular chaperone ATPase activity, glycoprotein-specific chaperone activity, N38, hsp70Ba, hsp70Bc, p42-MAPK, hsp70Bb, Hsp-c4, Reactive, dhsc70, study, Mkk3, MKK3, Nervous System, methods, DmelCG12244, Inclusions, experimental section, Transients, ms(3)08445, stubby, Grf-40, Nonmigrants, ridges, c-Jun N-terminal kinase activity, Maintenances, Crk-III, p42 mitogen-activated protein kinase activity, hsp70 87A, Neurodegenerative Disorders, Oxygen Species, hsp70 87C, Probabilities, ATP:protein phosphotransferase (MAPKK-activated) activity, non-neoplastic, Cytoplasmic, Squatter, Abstract, GRID, hsp89, Active Oxygen Species, hsp86, hsp84, hsp83, anon-WO0118547.237, disorder, neuronal cell death, hsp90, HIGM2, Long-Term Effect, Active Oxygen, Autoregulation, data, Pro Oxidants, JNK, Jnk, protein complex, RnBP, DMPK2, Map-6, hsp82, diencephalon, anon-sts23, GlcNAc 2-epimerase, P11/Hrb87F, medical condition, Crk-I, DMKK3/lic, DmelCG7393, Degenerative Neurologic Disorder, p38delta, HSC-70, jnk, hsp68, natural protein, Period, group 2, HSPC1, Protein, Nomad, MBP kinase I activity, hsp70, Active, clone 2.53, Hsp70(87C), protein complex assembly, flange, CG18743, Data Base, MAP-6, l(2)k16102, Hsp70.1, Degenerative Conditions, anon-WO0140519.209, mitogen activated kinase activity, E(nd)195, Mxi2, POLD4, Sapk2A, MAPK2, DMHSP82, HSPCA, dp38, Dorfin, Su(Raf)3A, Protein Gene Products, present in greater numbers in organism, activation of homeostatic process, mxi2, Hspcb, AL024147, ERT1, hsp 70, Hspca, renin-binding protein, Neurodegenerative Disease, BG:DS00797.3, MAP kinase 1 activity"],"pubmed_title_synonyms":["ATHSP70, Hsp86-1, hspca, l(3)L3929, Hsp70, Hsc-4, scd, protein, heat shock protein 70, E(sev)3A, C81438, DmelCG1242, HSP70, stc, APG-2, protein polypeptide chains, AL024080, Roles, LAP-2, Hsp110, Concepts, LAP2, protein aggregate, hsp4, irp94, DmelCG6489, DmelCG18743, HSP82, hsp70 Ba, anon-WO0068693, RY, Hsp89, DmelCG5834, hsc4, Hsp84, Hsp86, Hsp90, HSPH2, xhsp70, HS24/P52, proteins, DmelCG31359, E(sina)2, inhibition of homeostatic process, hspc1, Hsp70Bc, l(3)j5C2, Hsp70Bb, hsp70 Aa, Hsp70Bd, HSP90, GRP78, HSPN, Role Concepts, homeostasis, DmelCG31366, Hsp82, CG4264, hspn, HSP83, hsc70, HSP86, Hsp70b, HSPCAL1, HSPCAL4, Hsp70a, Hsp84-1, dHsp70, 89kDa, CG1242, HS24|P52, HSP70Bbb, Hsp70B, 83K HSP, en(lz)3C/4C, Hsp70A, Role Concept, positive regulation of homeostatic process, Dm-hsp70, git10, Role, ARABIDOPSIS HEAT SHOCK PROTEIN 70, HSC4, Hsc4, HSP90N, DmelCG4264, anon-EST:Liang-2.53, Hsp70-BC, Hsp70-Ab, HSP90A, hsp-70, 90kDa, Hsp70A7d, dhsp70, HSC70-4, CG6489, CG31449, 83, CG5834, l(3)j7A4, HSP89A, hs70, Gene, hsp70(87A), hsp70Ab, hsp70Aa, HEL-S-5a, AL022974, protein-containing complex, bs17d06.y1, 87A, Hsp70-1, polypeptide chain, hsp70RY, DMHSP7A2, swo1, Gene Products, hsp70Ba, hsp70Bc, hsp70Bb, Hsp-c4, hsp70Bb-prime, dhsc70, hsp90a, anatomical systems, DMHSP7D1, BAP74, Hsp 70, ms(3)08445, CG31359, Maintenances, hsp70 87A, Hsc70, hsp70 87C, CG31354, hsp89, HSC70, hsp86, hsp84, hsp83, negative regulation of homeostatic process, anon-WO0118547.237, Hsp-70Aa, hsp90, Hsc4p, CG31366, Autoregulation, protein complex, hsp82, Proteins, Hsp70ab, regulation of homeostatic process., Concept, hsp70A, HSC-70, hsp70B, E(csp)1545, EL52, 86kDa, hsp68, native protein, natural protein, hsc70-4, HSPC1, Protein, hsp70, clone 2.53, Hsp70(87C), CG18743, 143198_at, Hsp70.1, hsp70a, dhsp70Aa, hsp70b, anon-WO0140519.209, l(3)03550, lap2, E(nd)195, i190, DMHSP82, HSPCA, Su(Raf)3A, Protein Gene Products, Gene Proteins, DmHSP70AA, activation of homeostatic process, Hspcb, AL024147, hsp 70, ORF1, Hspca, DmelCG31449, Hsp70Bbc, HSP70Bc, Hsp70aB"],"pubmed_abstract_synonyms":["projections, ATHSP70, Hsp86-1, extracellular signal-regulated kinase activity, GrpL, GRPL, pp44mapk, SAPKa, Growth factor receptor-binding protein, Globular Protein Folding, CRKII, l(3)L3929, NURF38, Neurologic Diseases, Hsc-4, scd, beta-tubulin folding, p38-alpha, C81438, p38MAPK, p38a, p38ALPHA, Hog, protein polypeptide chains, Donor Artificial Insemination, STOP, LeMPK3, Neurologic Disorders, hnRNP A2/B1, p44mpk, CDA2, LAP-2, Dp38, Pro Oxidant, SAPK1, SAPK2, Mpk34C, JNK-46, hsp4, p38B, irp94, p38A, DmelCG6489, DiE, DmelCG18743, hsp70 Ba, Degenerative Condition, mapk14a, DBSK/JNK, pp42, Junk, hrp40, Nonmigrant, HSPH2, HS24/P52, hnRNP36, proteins, suprasegmental levels of nervous system, inhibition of homeostatic process, Hrb87Fa, Dm p38b, Transient, Hsp70Bc, Hrb85CD, Hsp70Bb, hsp70 Aa, chaperonin-mediated tubulin folding, Hsp70Bd, Oxygen, hrp36, HSPN, Degenerative Neurologic Disease, Grf40, Cytoplasmic Inclusions, Role Concepts, dMKK3, Homo sapiens disease, hspn, GRBLG, ESTS:186F5S, hsc70, DmMPK2, Hsp70b, suprasegmental structures, Hsp70a, Hsp84-1, anatomical protrusion, dJNK, 6.3.2.-, csbp, ERK-2, CG4634, 89kDa, CG1242, PMK-2, PMK-1, HS24|P52, HSP70Bbb, Hrb87f, PMK-3, partial functionality, Hsp70B, 83K HSP, CSBP, mature diencephalon, Cytoplasmic Inclusion, Hsp70A, Globular Protein, Role Concept, co-chaperonin activity, Double ring-finger protein, Dm-hsp70, git10, shelf, Role, Heterologous Insemination, Cellular, D-MPK2, GRAP-2, Protein Foldings, ARABIDOPSIS HEAT SHOCK PROTEIN 70, Migrants and Transients, DmelCG4264, DmelCG5475, Mek3, MEK3, DMEK3, Degenerative Diseases, Radical, Neurologic Disease, Neurodegenerative disease, c-Crk, projection, ridge, AGE, experimental procedures, hsp-70, NURF-38, CSBP2, Artificial Insemination, DJNK, co-chaperone activity, CSBP1, Globular Protein Foldings, 90kDa, Hsp70A7d, dhsp70, Csbp2, Migrants, HSC70-4, Csbp1, CG31449, CG5834, l(3)j7A4, D-p38 MAPK, Grf40 adapter protein, HSP89A, lamellae, Foldings, Degenerative Neurologic Disorders, hs70, impaired, AL022974, protein-containing complex, GRB-2-like protein, Exip, AID, process of organ, Aid, bs17d06.y1, lamella, 87A, PRKM15, Prkm8, Stable tubule-only polypeptide, dMPK2, hsp70RY, PRKM14, p38 MAPK, DMHSP7A2, Gene Products, sapk2a, disease or disorder, Globular, EXIP, dNURF, hsp70Bb-prime, aid, DmelCG5680, ERK, DJNK/bsk, PRKM1, Insemination, p38beta, PRKM2, hsp90a, Hrp36, anatomical systems, JTV1, p38Ka, STOP145, DMHSP7D1, BAP74, p38Kb, dysfunction, Hsp 70, JNK21B1|2, AI848995, Worker, PRKM8, CG31359, BC023857, Hsc70, CG31354, GRB2L, Cellular Inclusion, Neurologic, CG12749, Neurologic Degenerative Diseases, HEL-S-284, HSC70, Protein Folding, accidental cell death, Degenerative Neurologic Diseases, negative regulation of homeostatic process, Hsp-70Aa, Spinal Cord, HRP36, Pro-Oxidant, STK26, Hsc4p, p38-2, laminae, myelin basic protein kinase activity, Heterologous, CG31366, SAPK1c, Dp38b, Dp38a, RING finger protein 19A, SAPK2A, 2810411E12Rik, Neurologic Disorder, JNK3alpha1, Proteins, disorders, MAP-2 kinase activity, thalamencephalon, Protein GADS, function, encephalon, Hsp70ab, Cell, regulation of homeostatic process., Human Donor, Concept, DmMKK3, hsp70A, hsp70B, E(csp)1545, EL52, JNK/SAPK, PDIP38, N-acetyl-D-glucosamine 2-epimerase, 86kDa, native protein, JNK1, Inclusion Body, hsc70-4, p38MAPKK, D-JNK, JNK1A2, condition, 145-kDa STOP, Donor, regulation of homeostatic process, Death, p38 beta, organ process, 143198_at, Artificial, Nurf38, hsp70a, dhsp70Aa, hsp70b, l(3)03550, lap2, Arp2, ARP2, P42MAPK, i190, Crk1, Neurologic Degenerative Conditions, Crk3, Understanding, CSPB1, Body, SAPK1C, Gene Proteins, processes, DmHSP70AA, 38 kDa DNA polymerase delta interaction protein, having decreased function, D-MKK3, CRK1, ORF1, CG5680, Nomads, Pro-Oxidants, Central Nervous System, DmelCG31449, Hsp70Bbc, HSP70Bc, Hsp70aB, Nurf 38, sapk2, hspca, Mpk2, Mpk3, Hsp70, Crko, p42mapk, protein, Neurologic Degenerative Condition, heat shock protein 70, D-p38, E(sev)3A, BSK, Bsk, Crk-II, p38 alpha, NURF, neuron cell death, Neurodegenerative Diseases, DmelCG1242, between brain, dysfunctional, HSP70, stc, Readability, APG-2, DmelCG4634, AL024080, p38/NURF-38, diseases, Roles, Hsp110, Concepts, diseases and disorders, synganglion, LAP2, mitogen-activated protein kinase activity, Q14, Q16, protein aggregate, mpk2, RK, Donor Artificial, Nervous System Degenerative Diseases, Adapter protein GRID, HSP82, human disease, anon-WO0068693, RY, Migrant Worker, DMKK3, Hsp89, DmelCG5834, hsc4, Hsp84, long, MEK3/MKK3, Hsp86, Hsp90, xhsp70, DmelCG31359, E(sina)2, AI849689, Neurodegenerative Disorder, hspc1, HSPC322, Folding, l(3)j5C2, HSP90, MP kinase activity, 38, GRP78, Dmp38a, AHA1, Hematopoietic cell-associated adapter protein GrpL, Dmp38b, papilla, Neurologic Degenerative Disease, Squatters, DmelCG12749, MBP kinase II activity, homeostasis, c-Jun, P11, DmelCG31366, Hsp82, CG4264, necrosis, CG5475, Neuro-degenerative disease, HSP83, HSP86, HSPCAL1, HSPCAL4, D-junk, MAP kinase 2 activity, dHsp70, Oxygen Radical, lamina, flanges, ERK1, ERK2, A230093K24Rik, Erk2, Hrb2, D-P38a, GrbX, GRBX, betweenbrain, D-p38b, chaperone activity, shortened, JNK21B1/2, D-p38a, en(lz)3C/4C, p41mapk, positive regulation of homeostatic process, Syn, MAPK, RENBP, Migrant, Progressive neurodegenerative disorder, alpha-tubulin folding, Mtap6, P38, Workers, C14orf3, Oxygen Radicals, HSC4, Hsc4, CG12244, HRB87F/hrp36, HSP90N, Inclusion, SH3-SH2-SH3 adapter Mona, GADS, JTV-1, anon-EST:Liang-2.53, Hsp70-BC, Hsp70-Ab, shelves, HRB87F, Mona, p38alpha, common, p38, Prkm15, HSP90A, lacks function of type, Prkm14, low functionality, loss of, Proto-oncogene c-Crk, disease, Degenerative, spine, p41, p40, multichaperone pathway, DmelCG12304, CG6489, short, 186F5S, 83, BSK/DJNK, the brain, other disease, l(1)G0252, Cellular Inclusions, experimental, Bodies, CG7393, Gene, hsp70(87A), Reactive Oxygen Intermediates, hsp70Ab, hsp70Aa, HEL-S-5a, cerebral degeneration disease, Migrant Workers, interbrain, protrusion, CrkIII, Hsp70-1, p38Hog, dp38a, dp38b, Gads, polypeptide chain, chaperonin ATPase activity, swo1, non-chaperonin molecular chaperone ATPase activity, glycoprotein-specific chaperone activity, N38, hsp70Ba, hsp70Bc, p42-MAPK, hsp70Bb, Hsp-c4, Reactive, dhsc70, study, Mkk3, MKK3, Nervous System, methods, DmelCG12244, Inclusions, experimental section, Transients, ms(3)08445, stubby, Grf-40, Nonmigrants, ridges, c-Jun N-terminal kinase activity, Crk-III, p42 mitogen-activated protein kinase activity, Neurodegenerative Disorders, hsp70 87A, Oxygen Species, hsp70 87C, Probabilities, ATP:protein phosphotransferase (MAPKK-activated) activity, non-neoplastic, Cytoplasmic, Squatter, GRID, hsp89, Active Oxygen Species, hsp86, hsp84, hsp83, anon-WO0118547.237, disorder, neuronal cell death, HIGM2, hsp90, Active Oxygen, Autoregulation, data, Pro Oxidants, JNK, Jnk, RnBP, protein complex, DMPK2, Map-6, hsp82, diencephalon, anon-sts23, GlcNAc 2-epimerase, P11/Hrb87F, medical condition, Crk-I, DMKK3/lic, DmelCG7393, Degenerative Neurologic Disorder, p38delta, HSC-70, jnk, hsp68, natural protein, group 2, Protein, HSPC1, Nomad, MBP kinase I activity, hsp70, Active, clone 2.53, Hsp70(87C), protein complex assembly, flange, CG18743, MAP-6, l(2)k16102, Hsp70.1, Degenerative Conditions, anon-WO0140519.209, mitogen activated kinase activity, E(nd)195, Mxi2, POLD4, Sapk2A, MAPK2, DMHSP82, HSPCA, dp38, Dorfin, Protein Gene Products, Su(Raf)3A, activation of homeostatic process, mxi2, Hspcb, AL024147, ERT1, hsp 70, Hspca, renin-binding protein, Neurodegenerative Disease, BG:DS00797.3, MAP kinase 1 activity"],"additional_accession":[]},"is_claimable":false,"name":"Proctor2011_ProteinHomeostasis_NormalCondition","description":"\n      \n        \n      This model is from the article:\n      \n         Modelling the Role of the Hsp70/Hsp90 System in the Maintenance of Protein Homeostasis\n\n        \nProctor CJ,  Lorimer IAJ\n      PLoS ONE2011; 6(7): e22038.\n      doi:10.1371/journal.pone.0022038,\n      \n        Abstract:\n        \nNeurodegeneration is an age-related disorder which is characterised by the accumulation of aggregated protein and neuronal cell death. There are many different neurodegenerative diseases which are classified according to the specific proteins involved and the regions of the brain which are affected. Despite individual differences, there are common mechanisms at the sub-cellular level leading to loss of protein homeostasis. The two central systems in protein homeostasis are the chaperone system, which promotes correct protein folding, and the cellular proteolytic system, which degrades misfolded or damaged proteins. Since these systems and their interactions are very complex, we use mathematical modelling to aid understanding of the processes involved. The model developed in this study focuses on the role of Hsp70 (IPR00103) and Hsp90 (IPR001404) chaperones in preventing both protein aggregation and cell death. Simulations were performed under three different conditions: no stress; transient stress due to an increase in reactive oxygen species; and high stress due to sustained increases in reactive oxygen species. The model predicts that protein homeostasis can be maintained during short periods of stress. However, under long periods of stress, the chaperone system becomes overwhelmed and the probability of cell death pathways being activated increases. Simulations were also run in which cell death mediated by the JNK (P45983) and p38 (Q16539) pathways was inhibited. The model predicts that inhibiting either or both of these pathways may delay cell death but does not stop the aggregation process and that eventually cells die due to aggregated protein inhibiting proteasomal function. This problem can be overcome if the sequestration of aggregated protein into inclusion bodies is enhanced. This model predicts responses to reactive oxygen species-mediated stress that are consistent with currently available experimental data. The model can be used to assess specific interventions to reduce cell death due to impaired protein homeostasis.\n   \n        \n          Note:\n        \n         Simulations were performed under three different conditions: 1) normal condition (no stress), 2) moderate stress due to an increase in reactive oxygen species (ROS) i.e. ROS levels were increased by a factor of 4 at time=4hours for a period of 1 hour (not 2 hours as mentioned in the figure 5 legend of the reference publication. This is a typo in the paper and is clarified by the author) and 3) high stress due to sustained increase in reactive oxygen species (ROS) (here ROS increases with time).\n         The model that corresponds to the normal condition is submitted as a main model in the BioModels Database. The other two models, that corresponds to the moderate stress conditions and high stress conditions are available in SBML format as supporting files [go to Curation tab].\n         Supplementary figures S3 (normal condition), S4 (moderate stress condition) and S6 (high stress condition) are reproduced here. \n      \n    ","dates":{"last_modification":"2024-08-21","publication":"2024-09-02","submission":"2010-05-28"},"accession":"BIOMD0000000344","cross_references":{"pubmed":["21779370"],"chebi":["CHEBI:36080","CHEBI:26523","CHEBI:15422","CHEBI:16761"],"biomodels__db":["MODEL1005280000","BIOMD0000000344"],"go":["GO:0016311","GO:0016310","GO:0070841","GO:0051235","GO:0090261","GO:0051085","GO:0006461","GO:0006915","GO:0003773","GO:0052064","GO:0006412","GO:0005829","GO:0005634","GO:0043241","GO:0070628","GO:0009056","GO:0000502","GO:0006974","GO:0008219","GO:0043234","GO:0008287","GO:0000302","GO:0051087","GO:0070389","GO:0032986","GO:0042803","GO:0070206","GO:0032092","GO:0009058"],"kegg__compound":["C00562"],"taxonomy":["7711"],"uniprot":["P31749","Q9UNE7","Q00613","P45983","P28562","Q16539"],"interpro":["IPR001023","IPR001404","IPR012233"]}}