{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:54:41Z","timestamp":1768510481533,"version":"3.49.0"},"posted":{"date-parts":[[2024,2,4]]},"group-title":"Neuroscience","reference-count":90,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,2,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Missense mutations in the gene encoding the microtubule-associated protein tau cause autosomal dominant forms of frontotemporal dementia. Multiple models of frontotemporal dementia based on transgenic expression of human tau in experimental model organisms, including\n                  <jats:italic>Drosophila<\/jats:italic>\n                  , have been described. These models replicate key features of the human disease, but do not faithfully recreate the genetic context of the human disorder. Here we use CRISPR-Cas mediated gene editing to model frontotemporal dementia caused by the tau P301L mutation by creating the orthologous mutation, P251L, in the endogenous\n                  <jats:italic>Drosophila tau<\/jats:italic>\n                  gene. Flies heterozygous or homozygous for tau P251L display age-dependent neurodegeneration, metabolic defects and accumulate DNA damage in affected neurons. To understand the molecular events promoting neuronal dysfunction and death in knock-in flies we performed single-cell RNA sequencing on approximately 130,000 cells from brains of tau P251L mutant and control flies. We found that expression of disease-associated mutant tau altered gene expression cell autonomously in all neuronal cell types identified and non-cell autonomously in glial cells. Cell signaling pathways, including glial-neuronal signaling, were broadly dysregulated as were brain region and cell-type specific protein interaction networks and gene regulatory programs. In summary, we present here a genetic model of tauopathy, which faithfully recapitulates the genetic context and phenotypic features of the human disease and use the results of comprehensive single cell sequencing analysis to outline pathways of neurotoxicity and highlight the role of non-cell autonomous changes in glia.\n                <\/jats:p>","DOI":"10.1101\/2024.02.02.578624","type":"posted-content","created":{"date-parts":[[2024,2,4]],"date-time":"2024-02-04T18:25:11Z","timestamp":1707071111000},"source":"Crossref","is-referenced-by-count":0,"title":["Transcriptional programs mediating neuronal toxicity and altered glial-neuronal signaling in a\n                  <i>Drosophila<\/i>\n                  knock-in tauopathy model"],"prefix":"10.64898","author":[{"given":"Hassan","family":"Bukhari","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanitha","family":"Nithianandam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel A.","family":"Battaglia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Cicalo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Souvarish","family":"Sarkar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aram","family":"Comjean","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanhui","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"Leventhal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianjun","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0315-7970","authenticated-orcid":false,"given":"Mel B.","family":"Feany","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024020621350492000_2024.02.02.578624v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"2024020621350492000_2024.02.02.578624v1.2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4637-04.2005"},{"key":"2024020621350492000_2024.02.02.578624v1.3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2006265"},{"key":"2024020621350492000_2024.02.02.578624v1.4","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1550-17.2017"},{"key":"2024020621350492000_2024.02.02.578624v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.02.015"},{"key":"2024020621350492000_2024.02.02.578624v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90200-B"},{"key":"2024020621350492000_2024.02.02.578624v1.7","doi-asserted-by":"publisher","DOI":"10.3390\/biom6010009"},{"key":"2024020621350492000_2024.02.02.578624v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/srep23102"},{"key":"2024020621350492000_2024.02.02.578624v1.9","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.115.3.717"},{"key":"2024020621350492000_2024.02.02.578624v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02230-8"},{"key":"2024020621350492000_2024.02.02.578624v1.11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1012851108"},{"key":"2024020621350492000_2024.02.02.578624v1.12","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128"},{"key":"2024020621350492000_2024.02.02.578624v1.13","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2491-10.2010"},{"key":"2024020621350492000_2024.02.02.578624v1.14","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.34550"},{"key":"2024020621350492000_2024.02.02.578624v1.15","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4644(20000801)78:2<305::AID-JCB12>3.0.CO;2-W"},{"key":"2024020621350492000_2024.02.02.578624v1.16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0137691"},{"key":"2024020621350492000_2024.02.02.578624v1.17","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s40478-023-01624-8","article-title":"Human Alzheimer\u2019s disease reactive astrocytes exhibit a loss of homeostastic gene expression","volume":"11","year":"2023","journal-title":"Acta Neuropathol Commun"},{"key":"2024020621350492000_2024.02.02.578624v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.05.057"},{"key":"2024020621350492000_2024.02.02.578624v1.19","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.114.6.1179"},{"key":"2024020621350492000_2024.02.02.578624v1.20","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28769"},{"key":"2024020621350492000_2024.02.02.578624v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2013.03.002"},{"key":"2024020621350492000_2024.02.02.578624v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.06.026"},{"key":"2024020621350492000_2024.02.02.578624v1.23","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-186650"},{"key":"2024020621350492000_2024.02.02.578624v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410400204"},{"key":"2024020621350492000_2024.02.02.578624v1.25","doi-asserted-by":"publisher","DOI":"10.1126\/science.7754370"},{"key":"2024020621350492000_2024.02.02.578624v1.26","doi-asserted-by":"crossref","first-page":"3416","DOI":"10.1038\/s41467-021-23762-0","article-title":"Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer\u2019s disease","volume":"12","year":"2021","journal-title":"Nat Commun"},{"key":"2024020621350492000_2024.02.02.578624v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2015.11.039"},{"key":"2024020621350492000_2024.02.02.578624v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2014.07.005"},{"key":"2024020621350492000_2024.02.02.578624v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3639"},{"key":"2024020621350492000_2024.02.02.578624v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1528"},{"key":"2024020621350492000_2024.02.02.578624v1.31","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12213"},{"key":"2024020621350492000_2024.02.02.578624v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2003.12.015"},{"key":"2024020621350492000_2024.02.02.578624v1.33","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006254"},{"key":"2024020621350492000_2024.02.02.578624v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2004.08.007"},{"key":"2024020621350492000_2024.02.02.578624v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2021.07.012"},{"key":"2024020621350492000_2024.02.02.578624v1.36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006531200"},{"key":"2024020621350492000_2024.02.02.578624v1.37","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012418-012936"},{"key":"2024020621350492000_2024.02.02.578624v1.38","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41572-023-00447-0","article-title":"Frontotemporal lobar degeneration","volume":"9","year":"2023","journal-title":"Nat Rev Dis Primers"},{"key":"2024020621350492000_2024.02.02.578624v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.05.004"},{"key":"2024020621350492000_2024.02.02.578624v1.40","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1278"},{"key":"2024020621350492000_2024.02.02.578624v1.41","doi-asserted-by":"publisher","DOI":"10.1101\/lm.034363.114"},{"key":"2024020621350492000_2024.02.02.578624v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/369488a0"},{"key":"2024020621350492000_2024.02.02.578624v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(01)00487-7"},{"key":"2024020621350492000_2024.02.02.578624v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1074"},{"key":"2024020621350492000_2024.02.02.578624v1.45","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1515\/znc-1979-1-228","article-title":"Isolation of Anatomical Brain Mutants of Drosophila by Histological Means","volume":"34","year":"1979","journal-title":"Zeitschrift f\u00fcr Naturforschung C"},{"key":"2024020621350492000_2024.02.02.578624v1.46","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3233\/JAD-2002-4315","article-title":"Re-expression of cell cycle proteins induces neuronal cell death during Alzheimer\u2019s disease","volume":"4","year":"2002","journal-title":"J Alzheimers Dis"},{"key":"2024020621350492000_2024.02.02.578624v1.47","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.1038\/ncomms3986","article-title":"TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster","volume":"4","year":"2013","journal-title":"Nat Commun"},{"key":"2024020621350492000_2024.02.02.578624v1.48","doi-asserted-by":"publisher","DOI":"10.1007\/s000180300034"},{"key":"2024020621350492000_2024.02.02.578624v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(00)00221-9"},{"key":"2024020621350492000_2024.02.02.578624v1.50","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1111\/neup.12154","article-title":"Frontotemporal dementia with parkinsonism linked to chromosome 17 with the MAPT R406W mutation presenting with a broad distribution of abundant senile plaques","volume":"35","year":"2015","journal-title":"Neuropathology"},{"key":"2024020621350492000_2024.02.02.578624v1.51","doi-asserted-by":"crossref","first-page":"106255","DOI":"10.1016\/j.nbd.2023.106255","article-title":"The consequences of neurodegenerative disease on neuron-astrocyte metabolic and redox interactions","volume":"185","year":"2023","journal-title":"Neurobiol Dis"},{"key":"2024020621350492000_2024.02.02.578624v1.52","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s12915-022-01280-9","article-title":"Single-cell RNA sequencing of the retina in a model of retinitis pigmentosa reveals early responses to degeneration in rods and cones","volume":"20","year":"2022","journal-title":"BMC Biol"},{"key":"2024020621350492000_2024.02.02.578624v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.12.042"},{"key":"2024020621350492000_2024.02.02.578624v1.54","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2011.00778.x"},{"key":"2024020621350492000_2024.02.02.578624v1.55","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1186\/s12859-015-0816-5","article-title":"FoCo: a simple and robust quantification algorithm of nuclear foci","volume":"16","year":"2015","journal-title":"BMC Bioinformatics"},{"key":"2024020621350492000_2024.02.02.578624v1.56","doi-asserted-by":"crossref","first-page":"105770","DOI":"10.1016\/j.nbd.2022.105770","article-title":"FTD-associated mutations in Tau result in a combination of dominant and recessive phenotypes","volume":"170","year":"2022","journal-title":"Neurobiol Dis"},{"key":"2024020621350492000_2024.02.02.578624v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(89)90050-0"},{"key":"2024020621350492000_2024.02.02.578624v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2020.07.017"},{"key":"2024020621350492000_2024.02.02.578624v1.59","doi-asserted-by":"publisher","DOI":"10.1126\/science.1058189"},{"key":"2024020621350492000_2024.02.02.578624v1.60","doi-asserted-by":"publisher","DOI":"10.1126\/science.abk2432"},{"key":"2024020621350492000_2024.02.02.578624v1.61","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyab235"},{"key":"2024020621350492000_2024.02.02.578624v1.62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.21.8422"},{"key":"2024020621350492000_2024.02.02.578624v1.63","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkf496"},{"key":"2024020621350492000_2024.02.02.578624v1.64","doi-asserted-by":"publisher","DOI":"10.1146\/ANNUREV-NEURO-080317-0621333"},{"key":"2024020621350492000_2024.02.02.578624v1.65","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.12.003"},{"key":"2024020621350492000_2024.02.02.578624v1.66","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22288"},{"key":"2024020621350492000_2024.02.02.578624v1.67","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.jneumeth.2017.12.020","article-title":"A novel ex vivo method for measuring whole brain metabolism in model systems","volume":"296","year":"2018","journal-title":"J Neurosci Methods"},{"key":"2024020621350492000_2024.02.02.578624v1.68","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.11.036"},{"key":"2024020621350492000_2024.02.02.578624v1.69","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.58.3.383"},{"key":"2024020621350492000_2024.02.02.578624v1.70","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/j.neuron.2023.02.033","article-title":"Neuronal identity defines \u03b1-synuclein and tau toxicity","volume":"111","year":"2023","journal-title":"Neuron"},{"key":"2024020621350492000_2024.02.02.578624v1.71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905529106"},{"key":"2024020621350492000_2024.02.02.578624v1.72","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41531-020-00143-w","article-title":"Comparative proteomic analysis highlights metabolic dysfunction in \u03b1-synucleinopathy","volume":"6","year":"2020","journal-title":"NPJ Parkinsons Dis"},{"key":"2024020621350492000_2024.02.02.578624v1.73","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.neuroscience.2022.04.017","article-title":"Tau-Induced Elevation of the Activity-Regulated Cytoskeleton Associated Protein Arc1 Causally Mediates Neurodegeneration in the Adult Drosophila Brain","volume":"518","year":"2023","journal-title":"Neuroscience"},{"key":"2024020621350492000_2024.02.02.578624v1.74","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s40478-019-0723-5","article-title":"Early neuronal accumulation of DNA double strand breaks in Alzheimer\u2019s disease","volume":"7","year":"2019","journal-title":"Acta Neuropathol Commun"},{"key":"2024020621350492000_2024.02.02.578624v1.75","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.02907"},{"key":"2024020621350492000_2024.02.02.578624v1.76","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3390\/antiox11010022","article-title":"Pathophysiology of Lipid Droplets in Neuroglia","volume":"11","year":"2021","journal-title":"Antioxidants (Basel)"},{"key":"2024020621350492000_2024.02.02.578624v1.77","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-4772-0"},{"key":"2024020621350492000_2024.02.02.578624v1.78","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0194-1"},{"key":"2024020621350492000_2024.02.02.578624v1.79","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s12035-020-02109-8","article-title":"DNA Double-Strand Break Accumulation in Alzheimer\u2019s Disease: Evidence from Experimental Models and Postmortem Human Brains","volume":"58","year":"2021","journal-title":"Mol Neurobiol"},{"key":"2024020621350492000_2024.02.02.578624v1.80","doi-asserted-by":"publisher","DOI":"10.1007\/s004120050155"},{"key":"2024020621350492000_2024.02.02.578624v1.81","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.2012.0092"},{"key":"2024020621350492000_2024.02.02.578624v1.82","doi-asserted-by":"crossref","unstructured":"Verkhratsky A , Sofroniew MV , Messing A , deLanerolle NC , Rempe D , Rodr\u00edguez JJ , Nedergaard M . 2012. Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro 4.","DOI":"10.1042\/AN20120010"},{"key":"2024020621350492000_2024.02.02.578624v1.83","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.10.5129"},{"key":"2024020621350492000_2024.02.02.578624v1.84","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.09.033"},{"key":"2024020621350492000_2024.02.02.578624v1.85","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002600"},{"key":"2024020621350492000_2024.02.02.578624v1.86","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202154217"},{"key":"2024020621350492000_2024.02.02.578624v1.87","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410100203"},{"key":"2024020621350492000_2024.02.02.578624v1.88","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062382"},{"key":"2024020621350492000_2024.02.02.578624v1.89","doi-asserted-by":"crossref","first-page":"e85251","DOI":"10.7554\/eLife.85251","article-title":"Tau polarizes an aging transcriptional signature to excitatory neurons and glia","volume":"12","year":"2023","journal-title":"Elife"},{"key":"2024020621350492000_2024.02.02.578624v1.90","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.01.010"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.02.02.578624","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:53:50Z","timestamp":1768456430000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.02.02.578624"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,4]]},"references-count":90,"URL":"https:\/\/doi.org\/10.1101\/2024.02.02.578624","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1101\/gr.278576.123","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,2,4]]},"subtype":"preprint"}}