{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T12:01:26Z","timestamp":1783166486708,"version":"3.54.6"},"posted":{"date-parts":[[2023,3,27]]},"group-title":"Cell Biology","reference-count":103,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T00:00:00Z","timestamp":1679875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Aging is the most prominent risk factor for Alzheimer\u2019s disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in AD brains remain elusive. Here, we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains aging hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-Tau and A\u03b2, resembling those in AD patient and APP mouse brains. Quantitative tNeuron proteomics identify aging and AD-linked deficits in proteostasis and organelle homeostasis, most notably in endosome-lysosomal components. Lysosomal deficits in aged tNeurons, including constitutive lysosomal damage and ESCRT-mediated lysosomal repair defects, are exacerbated in AD tNeurons and linked to inflammatory cytokine secretion and cell death. Supporting lysosomal deficits\u2019 centrality in AD, compounds ameliorating lysosomal function reduce A\u03b2 deposits and cytokine secretion. Thus, the tNeuron model system reveals impaired lysosomal homeostasis as an early event of aging and AD.<\/jats:p>","DOI":"10.1101\/2023.03.27.534444","type":"posted-content","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T23:20:13Z","timestamp":1679959213000},"source":"Crossref","is-referenced-by-count":10,"title":["Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8302-2915","authenticated-orcid":false,"given":"Ching-Chieh","family":"Chou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Vest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A.","family":"Prado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Wilson-Grady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4291-413X","authenticated-orcid":false,"given":"Joao A.","family":"Paulo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Shibuya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Moran-Losada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Ting","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"Gygi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery W.","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Finley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Wernig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5893-0831","authenticated-orcid":false,"given":"Tony","family":"Wyss-Coray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2302-6943","authenticated-orcid":false,"given":"Judith","family":"Frydman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025011605551285000_2023.03.27.534444v2.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1141448"},{"key":"2025011605551285000_2023.03.27.534444v2.2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4001"},{"key":"2025011605551285000_2023.03.27.534444v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/nature11654"},{"key":"2025011605551285000_2023.03.27.534444v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.02.030"},{"key":"2025011605551285000_2023.03.27.534444v2.5","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1034410"},{"key":"2025011605551285000_2023.03.27.534444v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.06.005"},{"key":"2025011605551285000_2023.03.27.534444v2.7","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201005144"},{"key":"2025011605551285000_2023.03.27.534444v2.8","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0323-7"},{"key":"2025011605551285000_2023.03.27.534444v2.9","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-021-00098-4"},{"key":"2025011605551285000_2023.03.27.534444v2.10","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2000.0364"},{"key":"2025011605551285000_2023.03.27.534444v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.10.078"},{"key":"2025011605551285000_2023.03.27.534444v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2021.136338"},{"key":"2025011605551285000_2023.03.27.534444v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.09.063"},{"key":"2025011605551285000_2023.03.27.534444v2.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2018.12.003"},{"key":"2025011605551285000_2023.03.27.534444v2.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.05.004"},{"key":"2025011605551285000_2023.03.27.534444v2.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.09.001"},{"key":"2025011605551285000_2023.03.27.534444v2.17","doi-asserted-by":"publisher","DOI":"10.1038\/nature10202"},{"key":"2025011605551285000_2023.03.27.534444v2.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.04.004"},{"key":"2025011605551285000_2023.03.27.534444v2.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0075-7"},{"key":"2025011605551285000_2023.03.27.534444v2.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2022.11.010"},{"key":"2025011605551285000_2023.03.27.534444v2.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2022.04.018"},{"key":"2025011605551285000_2023.03.27.534444v2.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0101-9"},{"key":"2025011605551285000_2023.03.27.534444v2.23","doi-asserted-by":"publisher","DOI":"10.1038\/srep33047"},{"key":"2025011605551285000_2023.03.27.534444v2.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2011.11.005"},{"key":"2025011605551285000_2023.03.27.534444v2.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-017-0047-3"},{"key":"2025011605551285000_2023.03.27.534444v2.26","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21154"},{"key":"2025011605551285000_2023.03.27.534444v2.27","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1211-9"},{"key":"2025011605551285000_2023.03.27.534444v2.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0539-4"},{"key":"2025011605551285000_2023.03.27.534444v2.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1195-2"},{"key":"2025011605551285000_2023.03.27.534444v2.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0238-1"},{"key":"2025011605551285000_2023.03.27.534444v2.31","doi-asserted-by":"publisher","DOI":"10.1038\/nm0197-67"},{"key":"2025011605551285000_2023.03.27.534444v2.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06726-w"},{"key":"2025011605551285000_2023.03.27.534444v2.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05164-4"},{"key":"2025011605551285000_2023.03.27.534444v2.34","doi-asserted-by":"crossref","unstructured":"Radulovic, M. et al. ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. The EMBO journal (2018).","DOI":"10.1101\/313866"},{"key":"2025011605551285000_2023.03.27.534444v2.35","doi-asserted-by":"crossref","unstructured":"Skowyra, M.L. , Schlesinger, P.H. , Naismith, T.V. & Hanson, P.I . Triggered recruitment of ESCRT machinery promotes endolysosomal repair. Science (New York, N.Y.) 360 (2018).","DOI":"10.1126\/science.aar5078"},{"key":"2025011605551285000_2023.03.27.534444v2.36","doi-asserted-by":"publisher","DOI":"10.1126\/science.1247136"},{"key":"2025011605551285000_2023.03.27.534444v2.37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.1.83"},{"key":"2025011605551285000_2023.03.27.534444v2.38","doi-asserted-by":"publisher","DOI":"10.1023\/A:1009695221038"},{"key":"2025011605551285000_2023.03.27.534444v2.39","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1063871"},{"key":"2025011605551285000_2023.03.27.534444v2.40","doi-asserted-by":"crossref","unstructured":"Eapen, V.V. , Swarup, S. , Hoyer, M.J. , Paulo, J.A. & Harper, J.W . Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy. Elife 10 (2021).","DOI":"10.7554\/eLife.72328"},{"key":"2025011605551285000_2023.03.27.534444v2.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2017.11.012"},{"key":"2025011605551285000_2023.03.27.534444v2.42","doi-asserted-by":"publisher","DOI":"10.1038\/nature08710"},{"key":"2025011605551285000_2023.03.27.534444v2.43","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01084-8"},{"key":"2025011605551285000_2023.03.27.534444v2.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2012.10.036"},{"key":"2025011605551285000_2023.03.27.534444v2.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2024.03.030"},{"key":"2025011605551285000_2023.03.27.534444v2.46","doi-asserted-by":"crossref","unstructured":"Caramello, A. et al. Intra-cellular accumulation of amyloid is a marker of selective neuronal vulnerability in Alzheimer\u2019s disease. medRxiv, 2023.2011.2023.23298911 (2023).","DOI":"10.1101\/2023.11.23.23298911"},{"key":"2025011605551285000_2023.03.27.534444v2.47","doi-asserted-by":"publisher","DOI":"10.4161\/auto.6259"},{"key":"2025011605551285000_2023.03.27.534444v2.48","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.41"},{"key":"2025011605551285000_2023.03.27.534444v2.49","doi-asserted-by":"publisher","DOI":"10.1038\/nature11729"},{"key":"2025011605551285000_2023.03.27.534444v2.50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2121609119"},{"key":"2025011605551285000_2023.03.27.534444v2.51","doi-asserted-by":"publisher","DOI":"10.1177\/0891988706286226"},{"key":"2025011605551285000_2023.03.27.534444v2.52","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201847055"},{"key":"2025011605551285000_2023.03.27.534444v2.53","doi-asserted-by":"crossref","unstructured":"Benyair, R. et al. Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration. Autophagy Rep 2 (2023).","DOI":"10.1080\/27694127.2023.2166722"},{"key":"2025011605551285000_2023.03.27.534444v2.54","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41576-019-0100-z","article-title":"Induced pluripotent stem cells in disease modelling and drug discovery","volume":"20","year":"2019","journal-title":"Nat Rev Genet"},{"key":"2025011605551285000_2023.03.27.534444v2.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.10.014"},{"key":"2025011605551285000_2023.03.27.534444v2.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.11.006"},{"key":"2025011605551285000_2023.03.27.534444v2.57","doi-asserted-by":"crossref","unstructured":"Huh, C.J. et al. Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts. Elife 5 (2016).","DOI":"10.7554\/eLife.18648"},{"key":"2025011605551285000_2023.03.27.534444v2.58","doi-asserted-by":"crossref","unstructured":"Herdy, J. et al. Chemical modulation of transcriptionally enriched signaling pathways to optimize the conversion of fibroblasts into neurons. Elife 8 (2019).","DOI":"10.7554\/eLife.41356"},{"key":"2025011605551285000_2023.03.27.534444v2.59","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00773-z"},{"key":"2025011605551285000_2023.03.27.534444v2.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.07.030"},{"key":"2025011605551285000_2023.03.27.534444v2.61","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.10.3861"},{"key":"2025011605551285000_2023.03.27.534444v2.62","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.019265"},{"key":"2025011605551285000_2023.03.27.534444v2.63","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1510329112"},{"key":"2025011605551285000_2023.03.27.534444v2.64","doi-asserted-by":"crossref","unstructured":"Sanyal, A. , et al. Constitutive Endolysosomal Perforation in Neurons allows Induction of \u03b1-Synuclein Aggregation by Internalized Pre-Formed Fibrils. bioRxiv (2024).","DOI":"10.1101\/2023.12.30.573738"},{"key":"2025011605551285000_2023.03.27.534444v2.65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2315690121"},{"key":"2025011605551285000_2023.03.27.534444v2.66","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38501-w"},{"key":"2025011605551285000_2023.03.27.534444v2.67","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201201076"},{"key":"2025011605551285000_2023.03.27.534444v2.68","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.05.004"},{"key":"2025011605551285000_2023.03.27.534444v2.69","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201700359"},{"key":"2025011605551285000_2023.03.27.534444v2.70","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-017-0203-y"},{"key":"2025011605551285000_2023.03.27.534444v2.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.07.010"},{"key":"2025011605551285000_2023.03.27.534444v2.72","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101468"},{"key":"2025011605551285000_2023.03.27.534444v2.73","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2019.1695401"},{"key":"2025011605551285000_2023.03.27.534444v2.74","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29481-4"},{"key":"2025011605551285000_2023.03.27.534444v2.75","doi-asserted-by":"crossref","unstructured":"Zhu, S.Y. et al. Lysosomal quality control of cell fate: a novel therapeutic target for human diseases. Cell death & disease 11, 817 (2020).","DOI":"10.1038\/s41419-020-03032-5"},{"key":"2025011605551285000_2023.03.27.534444v2.76","doi-asserted-by":"crossref","unstructured":"Bonet-Ponce, L. et al. LRRK2 mediates tubulation and vesicle sorting from lysosomes. Sci Adv 6 (2020).","DOI":"10.1126\/sciadv.abb2454"},{"key":"2025011605551285000_2023.03.27.534444v2.77","first-page":"1211498","article-title":"Annexin A7 mediates lysosome repair independently of ESCRT-III","volume":"11","year":"2023","journal-title":"Front Cell Dev Biol"},{"key":"2025011605551285000_2023.03.27.534444v2.78","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2010.01135.x"},{"key":"2025011605551285000_2023.03.27.534444v2.79","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02261-4"},{"key":"2025011605551285000_2023.03.27.534444v2.80","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0179-y"},{"key":"2025011605551285000_2023.03.27.534444v2.81","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-014-0070-5"},{"key":"2025011605551285000_2023.03.27.534444v2.82","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.01.018"},{"key":"2025011605551285000_2023.03.27.534444v2.83","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00613-4"},{"key":"2025011605551285000_2023.03.27.534444v2.84","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1293766"},{"key":"2025011605551285000_2023.03.27.534444v2.85","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0101-y"},{"key":"2025011605551285000_2023.03.27.534444v2.86","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04295-4"},{"key":"2025011605551285000_2023.03.27.534444v2.87","doi-asserted-by":"crossref","unstructured":"Tanabe, K. et al. Transdifferentiation of human adult peripheral blood T cells into neurons. Proceedings of the National Academy of Sciences of the United States of America (2018).","DOI":"10.1073\/pnas.1720273115"},{"key":"2025011605551285000_2023.03.27.534444v2.88","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.1247"},{"key":"2025011605551285000_2023.03.27.534444v2.89","doi-asserted-by":"crossref","unstructured":"Nguyen, A.T. et al. UBE2O remodels the proteome during terminal erythroid differentiation. Science (New York, N.Y.) 357 (2017).","DOI":"10.1126\/science.aan0218"},{"key":"2025011605551285000_2023.03.27.534444v2.90","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/nxab005"},{"key":"2025011605551285000_2023.03.27.534444v2.91","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.2c00137"},{"key":"2025011605551285000_2023.03.27.534444v2.92","doi-asserted-by":"publisher","DOI":"10.1021\/ac026117i"},{"key":"2025011605551285000_2023.03.27.534444v2.93","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.8b05399"},{"key":"2025011605551285000_2023.03.27.534444v2.94","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.9b00759"},{"key":"2025011605551285000_2023.03.27.534444v2.95","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.9b00860"},{"key":"2025011605551285000_2023.03.27.534444v2.96","doi-asserted-by":"publisher","DOI":"10.1016\/1044-0305(94)80016-2"},{"key":"2025011605551285000_2023.03.27.534444v2.97","doi-asserted-by":"publisher","DOI":"10.1021\/pr800420s"},{"key":"2025011605551285000_2023.03.27.534444v2.98","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201200439"},{"key":"2025011605551285000_2023.03.27.534444v2.99","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.12.001"},{"key":"2025011605551285000_2023.03.27.534444v2.100","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2839"},{"key":"2025011605551285000_2023.03.27.534444v2.101","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3569"},{"key":"2025011605551285000_2023.03.27.534444v2.102","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015004"},{"key":"2025011605551285000_2023.03.27.534444v2.103","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-26640-w"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.03.27.534444","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:27:57Z","timestamp":1768451277000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.03.27.534444"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,27]]},"references-count":103,"URL":"https:\/\/doi.org\/10.1101\/2023.03.27.534444","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41556-025-01623-y","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2023,3,27]]},"subtype":"preprint"}}