The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 01 2020
16 01 2020
Historique:
received:
11
08
2019
accepted:
16
12
2019
entrez:
18
1
2020
pubmed:
18
1
2020
medline:
9
4
2020
Statut:
epublish
Résumé
Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.
Identifiants
pubmed: 31949159
doi: 10.1038/s41467-019-14082-5
pii: 10.1038/s41467-019-14082-5
pmc: PMC6965647
doi:
Substances chimiques
Proteome
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
319Subventions
Organisme : NIA NIH HHS
ID : R56 AG061869
Pays : United States
Organisme : NIA NIH HHS
ID : K76 AG054772
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG014449
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG032969
Pays : United States
Organisme : NIA NIH HHS
ID : K01 AG032364
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027990
Pays : United States
Organisme : NIH HHS
ID : U54 OD020355
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG067598
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG043375
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH110553
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG028811
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA186866
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG017617
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172546
Pays : United States
Références
Bartsch, T. & Wulff, P. The hippocampus in aging and disease: from plasticity to vulnerability. Neuroscience 309, 1–16 (2015).
pubmed: 26241337
doi: 10.1016/j.neuroscience.2015.07.084
pmcid: 26241337
Arnsten, A. F. Stress weakens prefrontal networks: molecular insults to higher cognition. Nat. Neurosci. 18, 1376–1385 (2015).
pubmed: 26404712
pmcid: 4816215
doi: 10.1038/nn.4087
McEwen, B. S. The brain on stress: toward an integrative approach to brain, body, and behavior. Perspect. Psychol. Sci. 8, 673–675 (2013).
pubmed: 25221612
pmcid: 4159187
doi: 10.1177/1745691613506907
Maras, P. M. & Baram, T. Z. Sculpting the hippocampus from within: stress, spines, and CRH. Trends Neurosci. 35, 315–324 (2012).
pubmed: 22386641
pmcid: 3423222
doi: 10.1016/j.tins.2012.01.005
Schwabe, L. Memory under stress: from single systems to network changes. Eur. J. Neurosci. 45, 478–489 (2017).
pubmed: 27862513
doi: 10.1111/ejn.13478
pmcid: 27862513
Querfurth, H. W. & LaFerla, F. M. Alzheimer’s disease. N. Engl. J. Med. 362, 329–344 (2010).
pubmed: 20107219
doi: 10.1056/NEJMra0909142
pmcid: 20107219
Brehme, M. et al. A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. Cell Rep. 9, 1135–1150 (2014).
pubmed: 25437566
pmcid: 4255334
doi: 10.1016/j.celrep.2014.09.042
Kaushik, S. & Cuervo, A. M. Proteostasis and aging. Nat. Med. 21, 1406–1415 (2015).
pubmed: 26646497
doi: 10.1038/nm.4001
pmcid: 26646497
Lindberg, I. et al. Chaperones in neurodegeneration. J. Neurosci. 35, 13853–13859 (2015).
pubmed: 26468185
pmcid: 4604223
doi: 10.1523/JNEUROSCI.2600-15.2015
Lindquist, S. L. & Kelly, J. W. Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases: progress and prognosis. Cold Spring Harb. Perspect. Biol. 3, a004507 (2011).
pubmed: 21900404
pmcid: 3225948
doi: 10.1101/cshperspect.a004507
Morimoto, R. I. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev. 22, 1427–1438 (2008).
pubmed: 18519635
pmcid: 2732416
doi: 10.1101/gad.1657108
Balchin, D., Hayer-Hartl, M. & Hartl, F. U. In vivo aspects of protein folding and quality control. Science 353, aac4354 (2016).
doi: 10.1126/science.aac4354
Dickey, C. A. et al. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J. Clin. Invest. 117, 648–658 (2007).
pubmed: 17304350
pmcid: 1794119
doi: 10.1172/JCI29715
Thompson, A. D. et al. Analysis of the tau-associated proteome reveals that exchange of Hsp70 for Hsp90 is involved in tau degradation. ACS Chem. Biol. 7, 1677–1686 (2012).
pubmed: 22769591
pmcid: 3477299
doi: 10.1021/cb3002599
Deture, M., Hicks, C. & Petrucelli, L. Targeting heat shock proteins in tauopathies. Curr. Alzheimer Res. 7, 677–684 (2010).
pubmed: 20678072
doi: 10.2174/156720510793611565
Wang, B. et al. A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer’s mouse model via an HSF1-mediated mechanism. Mol. Psychiatry 22, 990–1001 (2017).
pubmed: 27457810
doi: 10.1038/mp.2016.104
Rodina, A. et al. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 538, 397–401 (2016).
pubmed: 27706135
pmcid: 5283383
doi: 10.1038/nature19807
Joshi, S. et al. Adapting to stress - chaperome networks in cancer. Nat. Rev. Cancer 18, 562–575 (2018).
pubmed: 29795326
pmcid: 6108944
doi: 10.1038/s41568-018-0020-9
Kourtis, N. et al. Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia. Nat. Med. 24, 1157–1166 (2018).
pubmed: 30038221
pmcid: 6082694
doi: 10.1038/s41591-018-0105-8
Wang, T. et al. Chaperome heterogeneity and its implications for cancer study and treatment. J. Biol. Chem. 294, 2162–2179 (2019).
pubmed: 30409908
doi: 10.1074/jbc.REV118.002811
Kishinevsky, S. et al. HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons. Nat. Commun. 9, 4345 (2018).
pubmed: 30341316
pmcid: 6195591
doi: 10.1038/s41467-018-06486-6
Moulick, K. et al. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat. Chem. Biol. 7, 818–826 (2011).
pubmed: 21946277
pmcid: 3265389
doi: 10.1038/nchembio.670
Tai, W., Guzman, M. L. & Chiosis, G. The epichaperome: the power of many as the power of one. Oncoscience 3, 266–267 (2016).
pubmed: 28050576
pmcid: 5116943
Taldone, T. et al. A chemical biology approach to the chaperome in cancer-HSP90 and beyond. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a034116 (2019).
doi: 10.1101/cshperspect.a034116
pubmed: 30936118
Pillarsetty, N. et al. Paradigms for precision medicine in epichaperome cancer therapy. Cancer Cell 36, 559–573 (2019).
pubmed: 31668946
doi: 10.1016/j.ccell.2019.09.007
Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).
pubmed: 17270732
doi: 10.1016/j.neuron.2007.01.010
Carroll, J. C. et al. Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy. J. Neurosci. 31, 14436–14449 (2011).
pubmed: 21976528
pmcid: 3230070
doi: 10.1523/JNEUROSCI.3836-11.2011
Hu, W. et al. Hyperphosphorylation determines both the spread and the morphology of tau pathology. Alzheimers Dement. 12, 1066–1077 (2016).
pubmed: 27133892
doi: 10.1016/j.jalz.2016.01.014
Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H. & Del Tredici, K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 112, 389–404 (2006).
pubmed: 16906426
pmcid: 3906709
doi: 10.1007/s00401-006-0127-z
Hurtado, D. E. et al. A{beta} accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model. Am. J. Pathol. 177, 1977–1988 (2010).
pubmed: 20802182
pmcid: 2947292
doi: 10.2353/ajpath.2010.100346
Ganguly, A. et al. Hsc70 chaperone activity is required for the cytosolic slow axonal transport of synapsin. J. Cell Biol. 216, 2059–2074 (2017).
pubmed: 28559423
pmcid: 5496608
doi: 10.1083/jcb.201604028
Ho, V. M., Lee, J. A. & Martin, K. C. The cell biology of synaptic plasticity. Science 334, 623–628 (2011).
pubmed: 22053042
pmcid: 3286636
doi: 10.1126/science.1209236
Langille, J. J. & Brown, R. E. The synaptic theory of memory: a historical survey and reconciliation of recent opposition. Front Syst. Neurosci. 12, 52 (2018).
pubmed: 30416432
pmcid: 6212519
doi: 10.3389/fnsys.2018.00052
Lisman, J., Cooper, K., Sehgal, M. & Silva, A. J. Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability. Nat. Neurosci. 21, 309–314 (2018).
pubmed: 29434376
pmcid: 5915620
doi: 10.1038/s41593-018-0076-6
Nakahata, Y. & Yasuda, R. Plasticity of spine structure: local signaling, translation and cytoskeletal reorganization. Front. Synaptic Neurosci. 10, 29 (2018).
pubmed: 30210329
pmcid: 6123351
doi: 10.3389/fnsyn.2018.00029
Spence, E. F. & Soderling, S. H. Actin out: regulation of the synaptic cytoskeleton. J. Biol. Chem. 290, 28613–28622 (2015).
pubmed: 26453304
pmcid: 4661376
doi: 10.1074/jbc.R115.655118
Collingridge, G. L., Peineau, S., Howland, J. G. & Wang, Y. T. Long-term depression in the CNS. Nat. Rev. Neurosci. 11, 459–473 (2010).
pubmed: 20559335
doi: 10.1038/nrn2867
pmcid: 20559335
Kennedy, M. B. Synaptic signaling in learning and memory. Cold Spring Harb. Perspect. Biol. 8, a016824 (2013).
pubmed: 24379319
doi: 10.1101/cshperspect.a016824
pmcid: 24379319
Alberini, C. M. & Kandel, E. R. The regulation of transcription in memory consolidation. Cold Spring Harb. Perspect. Biol. 7, a021741 (2014).
pubmed: 25475090
doi: 10.1101/cshperspect.a021741
Bailey, C. H., Kandel, E. R. & Harris, K. M. Structural components of synaptic plasticity and memory consolidation. Cold Spring Harb. Perspect. Biol. 7, a021758 (2015).
pubmed: 26134321
pmcid: 4484970
doi: 10.1101/cshperspect.a021758
Kapur, M., Monaghan, C. E. & Ackerman, S. L. Regulation of mRNA translation in neurons-a matter of life and death. Neuron 96, 616–637 (2017).
pubmed: 29096076
pmcid: 5693308
doi: 10.1016/j.neuron.2017.09.057
Jung, H., Gkogkas, C. G., Sonenberg, N. & Holt, C. E. Remote control of gene function by local translation. Cell 157, 26–40 (2014).
pubmed: 24679524
pmcid: 3988848
doi: 10.1016/j.cell.2014.03.005
Carlezon, W. A. Jr., Duman, R. S. & Nestler, E. J. The many faces of CREB. Trends Neurosci. 28, 436–445 (2005).
pubmed: 15982754
doi: 10.1016/j.tins.2005.06.005
pmcid: 15982754
Kügler, S. et al. The X-linked inhibitor of apoptosis (XIAP) prevents cell death in axotomized CNS neurons in vivo. Cell Death Differ. 7, 815 (2000).
pubmed: 11042676
doi: 10.1038/sj.cdd.4400712
pmcid: 11042676
Neves, G., Cooke, S. F. & Bliss, T. V. Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat. Rev. Neurosci. 9, 65–75 (2008).
pubmed: 18094707
doi: 10.1038/nrn2303
pmcid: 18094707
Hyman, B. T., Van Hoesen, G. W., Damasio, A. R. & Barnes, C. L. Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225, 1168–1170 (1984).
pubmed: 6474172
doi: 10.1126/science.6474172
pmcid: 6474172
Hyman, B. T., Van Hoesen, G. W. & Damasio, A. R. Memory-related neural systems in Alzheimer’s disease: an anatomic study. Neurology 40, 1721–1730 (1990).
pubmed: 2234428
doi: 10.1212/WNL.40.11.1721
pmcid: 2234428
Lynch, M. A. Long-term potentiation and memory. Physiol. Rev. 84, 87–136 (2004).
pubmed: 14715912
doi: 10.1152/physrev.00014.2003
pmcid: 14715912
Samus Therapeutics I. A Single Ascending Dose Study to Evaluate the Safety and Pharmacokinetics of PU-AD in Healthy Subjects. ClinicalTrials.gov NCT03935568 (2019).
Ginsberg, S. D. et al. Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer’s disease. Hippocampus 29, 422–439 (2019).
pubmed: 28888073
doi: 10.1002/hipo.22802
Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019).
pubmed: 31042697
pmcid: 6865822
doi: 10.1038/s41586-019-1195-2
Rahman, M. R. et al. Network-based approach to identify molecular signatures and therapeutic agents in Alzheimer’s disease. Comput Biol. Chem. 78, 431–439 (2019).
pubmed: 30606694
doi: 10.1016/j.compbiolchem.2018.12.011
Mostafavi, S. et al. A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease. Nat. Neurosci. 21, 811–819 (2018).
pubmed: 29802388
pmcid: 6599633
doi: 10.1038/s41593-018-0154-9
De Jager, P. L., Yang, H. S. & Bennett, D. A. Deconstructing and targeting the genomic architecture of human neurodegeneration. Nat. Neurosci. 21, 1310–1317 (2018).
pubmed: 30258235
doi: 10.1038/s41593-018-0240-z
Roodveldt, C., Outeiro, T. F. & Braun, J. E. A. Editorial: Molecular chaperones and neurodegeneration. Front Neurosci. 11, 565 (2017).
pubmed: 29085276
pmcid: 5649153
doi: 10.3389/fnins.2017.00565
Mass, E. et al. A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature 549, 389–393 (2017).
pubmed: 28854169
pmcid: 6047345
doi: 10.1038/nature23672
Du, L. & Pertsemlidis, A. Cancer and neurodegenerative disorders: pathogenic convergence through microRNA regulation. J. Mol. Cell Biol. 3, 176–180 (2011).
pubmed: 21278200
pmcid: 3104012
doi: 10.1093/jmcb/mjq058
Taldone, T. et al. Radiosynthesis of the iodine-124 labeled Hsp90 inhibitor PU-H71. J. Label. Comp. Radiopharm. 59, 129–132 (2016).
doi: 10.1002/jlcr.3369
LaFerla, F. M. & Green, K. N. Animal models of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006320 (2012).
pubmed: 23002015
pmcid: 3543097
doi: 10.1101/cshperspect.a006320
Stover, K. R., Campbell, M. A., Van Winssen, C. M. & Brown, R. E. Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer’s disease. Behav. Brain Res. 289, 29–38 (2015).
pubmed: 25896362
doi: 10.1016/j.bbr.2015.04.012
Israel, M. A. et al. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216–220 (2012).
pubmed: 22278060
pmcid: 3338985
doi: 10.1038/nature10821
van der Kant, R. et al. Cholesterol metabolism is a druggable axis that independently regulates tau and amyloid-beta in iPSC-derived Alzheimer’s disease neurons. Cell Stem Cell 24, 1–13 (2019).
doi: 10.1016/j.stem.2018.12.010
Woodruff, G. et al. Defective transcytosis of APP and lipoproteins in human iPSC-derived neurons with familial Alzheimer’s disease mutations. Cell Rep. 17, 759–773 (2016).
pubmed: 27732852
pmcid: 5796664
doi: 10.1016/j.celrep.2016.09.034
Miller, J. D. et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13, 691–705 (2013).
pubmed: 24315443
pmcid: 24315443
doi: 10.1016/j.stem.2013.11.006
Lein, E. S. et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168–176 (2007).
pubmed: 17151600
doi: 10.1038/nature05453
Ciznadija, D., Zhu, X. H. & Koff A. Hdm2- and proteasome-dependent turnover limits p21 accumulation during S phase. Cell Cycle 10, 2714–2723 (2011).
Franklin, K. B. J. & Paxinos, G. Paxinos and Franklin’s the Mouse Brain in Stereotaxic Coordinates, Fourth edn. (Academic Press, 2013).
Tyanova, S., Temu, T. & Cox, J. The MaxQuant computational platform for mass spectrometry-based shotgun proteomics. Nat. Protoc. 11, 2301–2319 (2016).
pubmed: 27809316
doi: 10.1038/nprot.2016.136
Hadizadeh Esfahani, A., Sverchkova, A., Saez-Rodriguez, J., Schuppert, A. A. & Brehme, M. A systematic atlas of chaperome deregulation topologies across the human cancer landscape. PLoS Comput Biol. 14, e1005890 (2018).
pubmed: 29293508
pmcid: 5766242
doi: 10.1371/journal.pcbi.1005890