Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression
Open accessPublished version of a preprint
Abstract
Alternative splicing of the gene MAPT produces several isoforms of tau protein. Overexpression of these isoforms is characteristic of tauopathies, which are currently untreatable neurodegenerative diseases. Though non-canonical functions of tau have drawn interest, the role of tau isoforms in these diseases has not been fully examined and may reveal new details of tau-driven pathology. In particular, tau has been shown to promote activation of transposable elements—highly regulated nucleotide sequences that replicate throughout the genome and can promote immunologic responses and cellular stress. This study examined tau isoforms’ roles in promoting cell damage and dysregulation of genes and transposable elements at a family-specific and locus-specific level. We performed immunofluorescence, Western blot and cytotoxicity assays, along with paired-end RNA sequencing on differentiated SH-SY5Y cells infected with lentiviral constructs of tau isoforms and treated with amyloid-beta oligomers. Our transcriptomic findings were validated using publicly available RNA-sequencing data from Alzheimer’s disease, progressive supranuclear palsy and control human samples from the Accelerating Medicine’s Partnership for AD (AMP-AD). Significance for biochemical assays was determined using Wilcoxon ranked-sum tests and false discovery rate. Transcriptome analysis was conducted through DESeq2 and the TEToolkit suite available from the Hammell lab at Cold Spring Harbor Laboratory. Our analyses show overexpression of different tau isoforms and their interactions with amyloid-beta in SH-SY5Y cells result in isoform-specific changes in the transcriptome, with locus-specific transposable element dysregulation patterns paralleling those seen in patients with Alzheimer’s disease and progressive supranuclear palsy. Locus-level transposable element expression showed increased dysregulation of L1 and Alu sites, which have been shown to drive pathology in other neurological diseases. We also demonstrated differences in rates of cell death in SH-SY5Y cells depending on tau isoform overexpression. These results demonstrate the importance of examining tau isoforms’ role in neurodegeneration and of further examining transposable element dysregulation in tauopathies and its role in activating the innate immune system.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Subsequent reanalysis of the AMP-AD and ROSMAP data sets by other groups confirmed the initial findings of these studies.
“Subsequent reanalysis of the AMP-AD and ROSMAP data sets by other groups confirmed the initial findings of these studies (Grundman et al. 2021, Wahl et al. 2023).”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Grundman et al. 2021
The Methods say Grundman et al. reanalyzed RNA-sequencing data from the AMP-AD Knowledge Portal, and the Discussion says their TE-expression analysis largely confirmed earlier findings of ERV activation. The cited paper does not identify a ROSMAP reanalysis, so it supports the AMP-AD portion of the claim but not the claim about both datasets. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Zempel, H., Thies, E., Mandelkow, E., & Mandelkow, E.-M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2357-10.2010 · Cited by 686 · cited 1× · see citing works
“Moreover, there is evidence that Aβ may influence the localization of tau within neurons [38].”
BackgroundTau promotes neurodegeneration through global chromatin relaxation
Frost, B., Hemberg, M., Lewis, J., & Feany, M. B. (2014) · Nature Neuroscience · doi:10.1038/nn.3639 · Cited by 519 · cited 1× · see citing works
“Recent evidence shows that tau pathology can broadly impact the epigenome through heterochromatin relaxation and histone acetylation [7, 8, 12].”
BackgroundNuclear Tau, a Key Player in Neuronal DNA Protection
Sultan, A., Nesslany, F., Violet, M., Bégard, S., Loyens, A., Talahari, S., Mansuroglu, Z., Marzin, D., Sergeant, N., Humez, S., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.199976 · Cited by 421 · cited 1× · see citing works
“Tau deficiency has been previously linked to DNA damage, and overexpression of tau in tau-deficient models has been shown to decrease DNA damage [10, 11].”
BackgroundSun, W., Samimi, H., Gamez, M., Zare, H., & Frost, B. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0194-1 · Cited by 315 · cited 6× · see citing works
“Notably, treatment of tau-transgenic Drosophila with reverse transcriptase inhibitors to suppress TEs can result in marked phenotypic improvement and reduced cell death, presenting a potentially exciting new avenue for therapeutic approaches [13].”
BackgroundMethodResultInfluentialWan, Y.-W., Al-Ouran, R., Mangleburg, C. G., Perumal, T. M., Lee, T. V., Allison, K., Swarup, V., Funk, C. C., Gaiteri, C., Allen, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107908 · Cited by 295 · see citing works
Meier, S., Bell, M., Lyons, D. N., Rodriguez-Rivera, J., Ingram, A., Fontaine, S. N., Mechas, E., Chen, J., Wolozin, B., LeVine, H., et al. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.3029-15.2016 · Cited by 190 · see citing works
Flagged first, then by citations
Research works printed but not linked: 40
- [1]Lebouvier T, Pasquier F, Buée L. Update on tauopathies. Curr Opin Neurol. 2017 Dec; 30(6): 589– 98. doi: 10.1097/WCO.0000000000000502 28914736 · DOI
- [2]Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol. 2017 05; 133(5): 665– 704. doi: 10.1007/s00401-017-1707-9 28386764 PMC5390006 · DOI · Paper page
- [3]Adams SJ, DeTure MA, McBride M, Dickson DW, Petrucelli L. Three repeat isoforms of tau inhibit assembly of four repeat tau filaments. PLoS One. 2010 May 25; 5(5): e10810. doi: 10.1371/journal.pone.0010810 20520830 PMC2876030 · DOI
- [4]Lacovich V, Espindola SL, Alloatti M, Pozo Devoto V, Cromberg LE, Čarná ME, et al. Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons. J Neurosci. 2017 01 4; 37(1): 58– 69. doi: 10.1523/JNEUROSCI.2305-16.2016 28053030 PMC6705673 · DOI
- [5]Sealey MA, Vourkou E, Cowan CM, Bossing T, Quraishe S, Grammenoudi S, et al. Distinct phenotypes of three-repeat and four-repeat human tau in a transgenic model of tauopathy. Neurobiol Dis. 2017 Sep; 105: 74– 83. doi: 10.1016/j.nbd.2017.05.003 28502805 · DOI
- [6]Sotiropoulos I, Galas MC, Silva JM, Skoulakis E, Wegmann S, Maina MB, et al. Atypical, non-standard functions of the microtubule associated Tau protein. Acta Neuropathol Commun. 2017 Nov 29; 5(1): 91. doi: 10.1186/s40478-017-0489-6 29187252 PMC5707803 · DOI
- [8]Klein HU, McCabe C, Gjoneska E, Sullivan SE, Kaskow BJ, Tang A, et al. Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer’s human brains. Nat Neurosci. 2019 01; 22(1): 37– 46. doi: 10.1038/s41593-018-0291-1 30559478 PMC6516529 · DOI
- [11]Violet M, Delattre L, Tardivel M, Sultan A, Chauderlier A, Caillierez R, et al. A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front Cell Neurosci. 2014; 8: 84. doi: 10.3389/fncel.2014.00084 24672431 PMC3957276 · DOI · Paper page
- [12]Guo C, Jeong HH, Hsieh YC, Klein HU, Bennett DA, De Jager PL, et al. Tau Activates Transposable Elements in Alzheimer’s Disease. Cell Rep. 2018 06 5; 23(10): 2874– 80. doi: 10.1016/j.celrep.2018.05.004 29874575 PMC6181645 · DOI · Paper page
- [14]Payer LM, Burns KH. Transposable elements in human genetic disease. Nat Rev Genet. 2019 12; 20(12): 760– 72. doi: 10.1038/s41576-019-0165-8 31515540 · DOI
- [15]Klein SJ, O’Neill RJ. Transposable elements: genome innovation, chromosome diversity, and centromere conflict. Chromosome Res. 2018 03; 26(1–2): 5– 23. doi: 10.1007/s10577-017-9569-5 29332159 PMC5857280 · DOI
- [16]Muñoz-López M, García-Pérez JL. DNA transposons: nature and applications in genomics. Curr Genomics. 2010 Apr; 11(2): 115– 28. doi: 10.2174/138920210790886871 20885819 PMC2874221 · DOI
- [17]Tam OH, Ostrow LW, Gale Hammell M. Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease. Mob DNA. 2019; 10: 32. doi: 10.1186/s13100-019-0176-1 31372185 PMC6659213 · DOI
- [18]Götz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001 Aug 24; 293(5534): 1491– 5. doi: 10.1126/science.1062097 11520988 · DOI · Paper page
- [19]Rockenstein E, Overk CR, Ubhi K, Mante M, Patrick C, Adame A, et al. A novel triple repeat mutant tau transgenic model that mimics aspects of pick’s disease and fronto-temporal tauopathies. PLoS One. 2015; 10(3): e0121570. doi: 10.1371/journal.pone.0121570 25803611 PMC4372415 · DOI
- [20]Tiscornia G, Singer O, Verma IM. Production and purification of lentiviral vectors. Nat Protoc. 2006; 1(1): 241– 5. doi: 10.1038/nprot.2006.37 17406239 · DOI
- [21]Spencer B, Michael S, Shen J, Kosberg K, Rockenstein E, Patrick C, et al. Lentivirus mediated delivery of neurosin promotes clearance of wild-type α-synuclein and reduces the pathology in an α-synuclein model of LBD. Mol Ther. 2013 Jan; 21(1): 31– 41. doi: 10.1038/mt.2012.66 22508489 PMC3538325 · DOI
- [22]Kovalevich J, Langford D. Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol Biol. 2013; 1078: 9– 21. doi: 10.1007/978-1-62703-640-5_2 23975817 PMC5127451 · DOI · Paper page
- [23]Xicoy H, Wieringa B, Martens GJ. The SH-SY5Y cell line in Parkinson’s disease research: a systematic review. Mol Neurodegener. 2017 01 24; 12(1): 10. doi: 10.1186/s13024-017-0149-0 28118852 PMC5259880 · DOI · Paper page
- [24]Stine WB, Jungbauer L, Yu C, LaDu MJ. Preparing synthetic Aβ in different aggregation states. Methods Mol Biol. 2011; 670: 13– 32. doi: 10.1007/978-1-60761-744-0_2 20967580 PMC3752843 · DOI · Paper page
- [25]Allen M, Carrasquillo MM, Funk C, Heavner BD, Zou F, Younkin CS, et al. Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases. Sci Data. 2016 Oct 11; 3: 160089. doi: 10.1038/sdata.2016.89 27727239 PMC5058336 · DOI · Paper page
- [27]Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013 Jan 1; 29(1): 15– 21. doi: 10.1093/bioinformatics/bts635 23104886 PMC3530905 · DOI · Paper page
- [28]Okonechnikov K, Conesa A, García-Alcalde F. Qualimap 2: advanced multi-sample quality control for high-throughput sequencing data. Bioinformatics. 2016 Jan 15; 32(2): 292– 4. doi: 10.1093/bioinformatics/btv566 26428292 PMC4708105 · DOI · Paper page
- [29]Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014 Apr 1; 30(7): 923– 30. doi: 10.1093/bioinformatics/btt656 24227677 · DOI · Paper page
- [30]Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12): 550. doi: 10.1186/s13059-014-0550-8 25516281 PMC4302049 · DOI · Paper page
- [32]Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012 May; 16(5): 284– 7. doi: 10.1089/omi.2011.0118 22455463 PMC3339379 · DOI · Paper page
- [33]Reimand J, Isserlin R, Voisin V, Kucera M, Tannus-Lopes C, Rostamianfar A, et al. Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, Cytoscape and EnrichmentMap. Nat Protoc. 2019 02; 14(2): 482– 517. doi: 10.1038/s41596-018-0103-9 30664679 PMC6607905 · DOI · Paper page
- [34]Jin Y, Tam OH, Paniagua E, Hammell M. TEtranscripts: a package for including transposable elements in differential expression analysis of RNA-seq datasets. Bioinformatics. 2015 Nov 15; 31(22): 3593– 9. doi: 10.1093/bioinformatics/btv422 26206304 PMC4757950 · DOI
- [35]Jin Y, Hammell M. Analysis of RNA-Seq Data Using TEtranscripts. Methods Mol Biol. 2018; 1751: 153– 67. doi: 10.1007/978-1-4939-7710-9_11 29508296 · DOI
- [36]Ewels P, Magnusson M, Lundin S, Käller M. MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics. 2016 10 1; 32(19): 3047– 8. doi: 10.1093/bioinformatics/btw354 27312411 PMC5039924 · DOI · Paper page
- [37]Mansuroglu Z, Benhelli-Mokrani H, Marcato V, Sultan A, Violet M, Chauderlier A, et al. Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin. Sci Rep. 2016 09 8; 6: 33047. doi: 10.1038/srep33047 27605042 PMC5015075 · DOI · Paper page
- [39]Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G. Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim Biophys Acta. 2010 Jan; 1802(1): 2– 10. doi: 10.1016/j.bbadis.2009.10.006 19853658 · DOI · Paper page
- [40]Forner S, Baglietto-Vargas D, Martini AC, Trujillo-Estrada L, LaFerla FM. Synaptic Impairment in Alzheimer’s Disease: A Dysregulated Symphony. Trends Neurosci. 2017 06; 40(6): 347– 57. doi: 10.1016/j.tins.2017.04.002 28494972 · DOI · Paper page
- [41]Marques-Coelho D, Iohan LDCC, Melo de Farias AR, Flaig A, Lambert JC, Costa MR, et al. Differential transcript usage unravels gene expression alterations in Alzheimer’s disease human brains. NPJ Aging Mech Dis. 2021 Jan 4; 7(1): 2. doi: 10.1038/s41514-020-00052-5 33398016 PMC7782705 · DOI
- [42]Milind N, Preuss C, Haber A, Ananda G, Mukherjee S, John C, et al. Transcriptomic stratification of late-onset Alzheimer’s cases reveals novel genetic modifiers of disease pathology. PLoS Genet. 2020 06; 16(6): e1008775. doi: 10.1371/journal.pgen.1008775 32492070 PMC7295244 · DOI
- [43]Morabito S, Miyoshi E, Michael N, Swarup V. Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer’s disease. Hum Mol Genet. 2020 10 10; 29(17): 2899– 919. doi: 10.1093/hmg/ddaa182 32803238 PMC7566321 · DOI · Paper page
- [45]Terry DM, Devine SE. Aberrantly High Levels of Somatic LINE-1 Expression and Retrotransposition in Human Neurological Disorders. Front Genet. 2019; 10: 1244. doi: 10.3389/fgene.2019.01244 31969897 PMC6960195 · DOI
- [46]Schoch KM, DeVos SL, Miller RL, Chun SJ, Norrbom M, Wozniak DF, et al. Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model. Neuron. 2016 06 1; 90(5): 941– 7. doi: 10.1016/j.neuron.2016.04.042 27210553 PMC5040069 · DOI · Paper page
- [47]Shanbhag NM, Evans MD, Mao W, Nana AL, Seeley WW, Adame A, et al. Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease. Acta Neuropathol Commun. 2019 05 17; 7(1): 77. doi: 10.1186/s40478-019-0723-5 31101070 PMC6524256 · DOI · Paper page
- [48]O’Neill K, Brocks D, Hammell MG. Mobile genomics: tools and techniques for tackling transposons. Philos Trans R Soc Lond B Biol Sci. 2020 03 30; 375(1795): 20190345. doi: 10.1098/rstb.2019.0345 32075565 PMC7061981 · DOI
Cited by
Sorted by citations
Frost, B., & Dubnau, J. (2024) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-082823-020615 · Cited by 45 · see citing works
Vallés-Saiz, L., Ávila, J., & Hernández, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311144 · Cited by 35 · see citing works
- Authors
- Grundman, J., Spencer, B., Sarsoza, F., & Rissman, R. A.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Rissman, Robert A.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2021-09-29
- Volume
- 16
- Issue
- 9
- Pages
- e0251611
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC8480850
- OpenAlex
- W3203173536
- Cited by
- 27
- References
- 7
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 11 · 2023: 3 · 2022: 2 · 2021: 1
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS ONE (publishedVersion, public-domain)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (RF1 AG072053, RF1 AG065385, R01 AG018440, P30 AG062429)
- Veterans Affairs San Diego Healthcare System (I01 BX003040, I01 BX004312)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau isoforms, MAPT, transposable elements, tauopathy, Alzheimer's disease, progressive supranuclear palsy, amyloid-beta oligomers, Alu elements, gene expression dysregulation, neurodegeneration, cell death, innate immune activation, SH-SY5Y cells
- MeSH terms
- Alzheimer Disease, Cell Line, DNA Transposable Elements, Gene Expression Regulation, Humans, Supranuclear Palsy, Progressive, Transfection, Case-Control Studies, Lentivirus, Amyloid beta-Peptides, tau Proteins, Alternative Splicing, Sequence Analysis, RNA, Protein Isoforms, Gene Expression Profiling
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
