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Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP

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Jiang, Shan, Wen, Natalie, Li, Zeran, Dube, Umber, Del Aguila, Jorge, Budde, John, Martinez, Rita, Hsu, Simon +7 more·2018·Translational Psychiatry
DOI 10.1038/s41398-018-0319-zPMC PMC6293323
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Abstract

Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau).MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P < 1 × 10−3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.

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  • iPSC-based models derived from individuals with a MAPT mutation indicate molecular mechanisms underlying tauopathies.

    “Despite this limitation, iPSC-based models derived from individuals with a MAPT mutation indicate molecular mechanisms underlying tauopathies (Gonzalez et al., 2018; lovino et al., 2015; Jiang et al., 2018; Nakamura et al., 2019; Silva et al., 2016, 2020; Wray, 2017).”

    From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Jiang et al., 2018

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  1. [1]Cairns NJ Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration Acta Neuropathol. 2007 114 5 22 10.1007/s00401-007-0237-2 17579875 PMC2827877 · DOI · Paper page
  2. [2]Mackenzie IR Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update Acta Neuropathol. 2010 119 1 4 10.1007/s00401-009-0612-2 19924424 PMC2799633 · DOI · Paper page
  3. [3]Yasuda M A mutation in the microtubule-associated protein tau in pallido-nigro-luysian degeneration Neurology 1999 53 864 868 10.1212/WNL.53.4.864 10489057 · DOI
  4. [4]Ghetti B Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging Neuropathol. Appl. Neurobiol. 2015 41 24 46 10.1111/nan.12213 25556536 PMC4329416 · DOI
  5. [5]Forrest SL Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies Brain 2018 141 521 534 10.1093/brain/awx328 29253099 PMC5888940 · DOI
  6. [6]Cruts M Theuns J Van Broeckhoven C Locus-specific mutation databases for neurodegenerative brain diseases Hum. Mutat. 2012 33 1340 1344 10.1002/humu.22117 22581678 PMC3465795 · DOI
  7. [7]van Swieten J Spillantini MG Hereditary frontotemporal dementia caused by Tau gene mutations Brain. Pathol. 2007 17 63 73 10.1111/j.1750-3639.2007.00052.x 17493040 PMC8095608 · DOI · Paper page
  8. [8]Reed LA Autosomal dominant dementia with widespread neurofibrillary tangles Ann. Neurol. 1997 42 564 572 10.1002/ana.410420406 9382467 · DOI
  9. [9]van Swieten JC Phenotypic variation in hereditary frontotemporal dementia with tau mutations Ann. Neurol. 1999 46 617 626 10.1002/1531-8249(199910)46:4<617::AID-ANA10>3.0.CO;2-I 10514099 · DOI · Paper page
  10. [10]Lindquist SG Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation Eur. J. Neurol. 2008 15 377 385 10.1111/j.1468-1331.2008.02069.x 18284428 · DOI
  11. [11]Miyasaka T Molecular analysis of mutant and wild-type tau deposited in the brain affected by the FTDP-17 R406W mutation Am. J. Pathol. 2001 158 373 379 10.1016/S0002-9440(10)63979-X 11159174 PMC1850291 · DOI
  12. [12]Zhang B Retarded axonal transport of R406W mutant tau in transgenic mice with a neurodegenerative tauopathy J. Neurosci. 2004 24 4657 4667 10.1523/JNEUROSCI.0797-04.2004 15140937 PMC6729383 · DOI
  13. [13]Tatebayashi Y Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau Proc. Natl Acad. Sci. USA 2002 99 13896 13901 10.1073/pnas.202205599 12368474 PMC129794 · DOI
  14. [14]Bunker JM Kamath K Wilson L Jordan MA Feinstein SC FTDP-17 mutations compromise the ability of tau to regulate microtubule dynamics in cells J. Biol. Chem. 2006 281 11856 11863 10.1074/jbc.M509420200 16495230 · DOI
  15. [15]Aoyagi H Hasegawa M Tamaoka A Fibrillogenic nuclei composed of P301L mutant tau induce elongation of P301L tau but not wild-type tau J. Biol. Chem. 2007 282 20309 20318 10.1074/jbc.M611876200 17526496 · DOI
  16. [16]Chang E Kim S Yin H Nagaraja HN Kuret J Pathogenic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps J. Neurochem. 2008 107 1113 1123 18803694 PMC2596975
  17. [17]Brandt R Leger J Lee G Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain J. Cell Biol. 1995 131 1327 1340 10.1083/jcb.131.5.1327 8522593 PMC2120645 · DOI
  18. [18]Gauthier-Kemper A The frontotemporal dementia mutation R406W blocks tau’s interaction with the membrane in an annexin A2-dependent manner J. Cell Biol. 2011 192 647 661 10.1083/jcb.201007161 21339331 PMC3044115 · DOI
  19. [19]Takahashi K Yamanaka S Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors Cell 2006 126 663 676 10.1016/j.cell.2006.07.024 16904174 · DOI · Paper page
  20. [20]Ban H Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors Proc. Natl Acad. Sci. USA 2011 108 14234 14239 10.1073/pnas.1103509108 21821793 PMC3161531 · DOI
  21. [21]Budde, J. et al. Precision genome-editing with CRISPR/Cas9 in human induced pluripotent stem cells. bioRxiv 187377 (2017).
  22. [22]Karch CM Expression of novel Alzheimer’s disease risk genes in control and Alzheimer’s disease brains PLoS ONE 2012 7 e50976 10.1371/journal.pone.0050976 23226438 PMC3511432 · DOI · Paper page
  23. [23]Li Z Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure Genome Med. 2018 10 43 10.1186/s13073-018-0551-4 29880032 PMC5992755 · DOI · Paper page
  24. [24]Allen M Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases Sci. Data 2016 3 160089 10.1038/sdata.2016.89 27727239 PMC5058336 · DOI · Paper page
  25. [25]Dobin Alexander Davis Carrie A. Schlesinger Felix Drenkow Jorg Zaleski Chris Jha Sonali Batut Philippe Chaisson Mark Gingeras Thomas R. STAR: ultrafast universal RNA-seq aligner Bioinformatics 2012 29 1 15 21 10.1093/bioinformatics/bts635 23104886 PMC3530905 · DOI · Paper page
  26. [26]Robinson JT Integrative genomics viewer Nat. Biotechnol. 2011 29 24 26 10.1038/nbt.1754 21221095 PMC3346182 · DOI · Paper page
  27. [27]Li H Durbin R Fast and accurate short read alignment with Burrows-Wheeler transform Bioinformatics 2009 25 1754 1760 10.1093/bioinformatics/btp324 19451168 PMC2705234 · DOI · Paper page
  28. [28]McKenna A The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data Genome Res. 2010 20 1297 1303 10.1101/gr.107524.110 20644199 PMC2928508 · DOI · Paper page
  29. [29]Patro R Duggal G Love MI Irizarry RA Kingsford C Salmon provides fast and bias-aware quantification of transcript expression Nat. Methods 2017 14 417 419 10.1038/nmeth.4197 28263959 PMC5600148 · DOI · Paper page
  30. [30]Love MI Huber W Anders S Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol. 2014 15 550 10.1186/s13059-014-0550-8 25516281 PMC4302049 · DOI · Paper page
  31. [33]Gaujoux R Seoighe C CellMix: a comprehensive toolbox for gene expression deconvolution Bioinformatics 2013 29 2211 2212 10.1093/bioinformatics/btt351 23825367 · DOI
  32. [34]Gaujoux R Seoighe C Semi-supervised Nonnegative Matrix Factorization for gene expression deconvolution: a case study Infect. Genet. Evol. 2012 12 913 921 10.1016/j.meegid.2011.08.014 21930246 · DOI
  33. [35]Montojo J GeneMANIA Cytoscape plugin: fast gene function predictions on the desktop Bioinformatics 2010 26 2927 2928 10.1093/bioinformatics/btq562 20926419 PMC2971582 · DOI
  34. [36]Wang J Vasaikar S Shi Z Greer M Zhang B WebGestalt 2017: a more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit Nucleic Acids Res. 2017 45 W1 W130 W137 10.1093/nar/gkx356 28472511 PMC5570149 · DOI
  35. [37]Matarin M A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology Cell Rep. 2015 10 633 644 10.1016/j.celrep.2014.12.041 25620700 · DOI · Paper page
  36. [38]Kang HJ Spatio-temporal transcriptome of the human brain Nature 2011 478 483 489 10.1038/nature10523 22031440 PMC3566780 · DOI · Paper page
  37. [40]Zhang K Cui S Chang S Zhang L Wang J i-GSEA4GWAS: a web server for identification of pathways/gene sets associated with traits by applying an improved gene set enrichment analysis to genome-wide association study Nucleic Acids Res. 2010 38 Web Server issue W90 W95 10.1093/nar/gkq324 20435672 PMC2896119 · DOI
  38. [41]Jiang S A systems view of the differences between APOE epsilon4 carriers and non-carriers in Alzheimer’s disease Front. Aging Neurosci. 2016 8 171 27462267 PMC4941795
  39. [43]Kilpinen H Common genetic variation drives molecular heterogeneity in human iPSCs Nature 2017 546 370 375 10.1038/nature22403 28489815 PMC5524171 · DOI · Paper page
  40. [45]Hevner RF Layer-specific markers as probes for neuron type identity in human neocortex and malformations of cortical development J. Neuropathol. Exp. Neurol. 2007 66 101 109 10.1097/nen.0b013e3180301c06 17278994 · DOI
  41. [46]Rohrer JD Structural brain imaging in frontotemporal dementia Biochim. Biophys. Acta 2012 1822 325 332 10.1016/j.bbadis.2011.07.014 21839829 · DOI
  42. [47]Seeley WW Selective functional, regional, and neuronal vulnerability in frontotemporal dementia Curr. Opin. Neurol. 2008 21 701 707 10.1097/WCO.0b013e3283168e2d 18989116 PMC2909835 · DOI
  43. [48]Seeley WW Anterior insula degeneration in frontotemporal dementia Brain Struct. Funct. 2010 214 465 475 10.1007/s00429-010-0263-z 20512369 PMC2886907 · DOI · Paper page
  44. [49]Tafoya LC Expression and function of SNAP-25 as a universal SNARE component in GABAergic neurons J. Neurosci. 2006 26 7826 7838 10.1523/JNEUROSCI.1866-06.2006 16870728 PMC6674219 · DOI
  45. [50]Dickson DW Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration J. Neurol. 1999 246 Suppl 2 II6 II15 10.1007/BF03161076 10525997 · DOI
  46. [51]Höglinger, G. U. et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat. Genet.43, 699 (2011). PMC3125476 21685912
  47. [54]Lujan R Shigemoto R Lopez-Bendito G Glutamate and GABA receptor signalling in the developing brain Neuroscience 2005 130 567 580 10.1016/j.neuroscience.2004.09.042 15590141 · DOI
  48. [55]Schwab C Yu S Wong W McGeer EG McGeer PL GAD65, GAD67, and GABAT immunostaining in human brain and apparent GAD65 loss in Alzheimer’s disease J. Alzheimers Dis. 2013 33 1073 1088 10.3233/JAD-2012-121330 23114513 · DOI
  49. [56]Piccini A APache Is an AP2-Interacting Protein Involved in Synaptic Vesicle Trafficking and Neuronal Development Cell Rep. 2017 21 3596 3611 10.1016/j.celrep.2017.11.073 29262337 · DOI
  50. [57]Levenga J Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments Acta Neuropathol. Commun. 2013 1 34 10.1186/2051-5960-1-34 24252661 PMC3893396 · DOI
  51. [58]Fong H Genetic correction of tauopathy phenotypes in neurons derived from human induced pluripotent stem cells Stem Cell Rep. 2013 1 226 234 10.1016/j.stemcr.2013.08.001 PMC3849235 24319659 · DOI · Paper page
  52. [59]Pir GJ Choudhary B Mandelkow E Mandelkow EM Tau mutant A152T, a risk factor for FTD/PSP, induces neuronal dysfunction and reduced lifespan independently of aggregation in a C. elegans Tauopathy model Mol. Neurodegener. 2016 11 33 10.1186/s13024-016-0096-1 27118310 PMC4847334 · DOI
  53. [60]Nykanen NP Kysenius K Sakha P Tammela P Huttunen HJ gamma-Aminobutyric acid type A (GABAA) receptor activation modulates tau phosphorylation J. Biol. Chem. 2012 287 6743 6752 10.1074/jbc.M111.309385 22235112 PMC3307276 · DOI
  54. [61]Ferrer I Neurons and their dendrites in frontotemporal dementia Dement. Geriatr. Cogn. Disord. 1999 10 Suppl 1 55 60 10.1159/000051214 10436342 · DOI
  55. [62]Levy R Alterations of GABAergic neurons in the basal ganglia of patients with progressive supranuclear palsy: an in situ hybridization study of GAD67 messenger RNA Neurology 1995 45 127 134 10.1212/WNL.45.1.127 7824102 · DOI
  56. [63]Foster NL PET measures of benzodiazepine receptors in progressive supranuclear palsy Neurology 2000 54 1768 1773 10.1212/WNL.54.9.1768 10802782 · DOI
  57. [64]Murley AG Rowe JB Neurotransmitter deficits from frontotemporal lobar degeneration Brain 2018 141 1263 1285 10.1093/brain/awx327 29373632 PMC5917782 · DOI
  58. [65]Neary D Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria Neurology 1998 51 1546 1554 10.1212/WNL.51.6.1546 9855500 · DOI · Paper page
  59. [66]Boxer AL Miller BL Clinical features of frontotemporal dementia Alzheimer Dis. Assoc. Disord. 2005 19 Suppl 1 S3 S6 10.1097/01.wad.0000183086.99691.91 16317256 · DOI
  60. [67]Solas M Puerta E Ramirez MJ Treatment options in alzheimer s disease: the GABA story Curr. Pharm. Des. 2015 21 4960 4971 10.2174/1381612821666150914121149 26365140 · DOI
  61. [68]Hoglinger GU Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy Nat. Genet. 2011 43 699 705 10.1038/ng.859 21685912 PMC3125476 · DOI · Paper page
  62. [69]Stefansson H A common inversion under selection in Europeans Nat. Genet. 2005 37 129 137 10.1038/ng1508 15654335 · DOI
  63. [70]Simon-Sanchez J Genome-wide association study reveals genetic risk underlying Parkinson’s disease Nat. Genet. 2009 41 1308 1312 10.1038/ng.487 19915575 PMC2787725 · DOI
  64. [71]Soler H The GABAergic septohippocampal connection is impaired in a mouse model of tauopathy Neurobiol. Aging 2017 49 40 51 10.1016/j.neurobiolaging.2016.09.006 27743524 · DOI
  65. [72]Loreth D Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy Neurobiol. Dis. 2012 47 1 12 10.1016/j.nbd.2012.03.011 22426397 · DOI
  66. [73]Zhang B Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease Cell 2013 153 707 720 10.1016/j.cell.2013.03.030 23622250 PMC3677161 · DOI · Paper page
  67. [74]Readhead B Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron. 2018 99 64 82.e7 10.1016/j.neuron.2018.05.023 29937276 PMC6551233 · DOI · Paper page

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Authors
Jiang, S., Wen, N., Li, Z., Dube, U., Del Aguila, J., Budde, J., Martinez, R., Hsu, S., Fernandez, M. V., Cairns, N. J., Dominantly Inherited Alzheimer Network (DIAN), International FTD-Genomics Consortium (IFGC), Harari, O., Cruchaga, C., & Karch, C. M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
  • Harari, Oscar
  • Cruchaga, Carlos
  • Karch, Celeste M.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2018-12-13
Volume
8
Issue
1
Pages
265-265
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-018-0319-z
PMC
PMC6293323
OpenAlex
W2903533912
Cited by
73
References
7
Citations by year
2026: 8 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 12 · 2021: 13 · 2020: 10 · 2019: 7
FWCI
5.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (K01 AG046374, R01 AG056293, R01 AG056923, R01 AG044546, P01 AG003991, RF1 AG053303)
  • Alzheimer's Association (NIRG-11-200110, BAND-14-338165)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
progressive supranuclear palsy, tauopathy, iPSC-derived neurons, GABA receptors, GABRB2, GABRG2, presynaptic signaling, synaptic dysfunction, gene expression profiling, frontotemporal dementia
MeSH terms
Aged, Aged, 80 and over, Animals, Brain, Female, Humans, Male, Mice, Inbred C57BL, Neurons, Supranuclear Palsy, Progressive, Signal Transduction, tau Proteins, Receptors, GABA, Induced Pluripotent Stem Cells, Frontotemporal Lobar Degeneration, Transcriptome, CRISPR-Cas Systems

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