{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:31:19Z","timestamp":1790937079703,"version":"4.1.0"},"reference-count":91,"publisher":"National Academy of Sciences","issue":"49","license":[{"start":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T00:00:00Z","timestamp":1669593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["AG065628"],"award-info":[{"award-number":["AG065628"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,12,6]]},"abstract":"<jats:p>\n                    Impairments in neural lysosomal- and autophagic-mediated degradation of cellular debris contribute to neuritic dystrophy and synaptic loss. While these are well-characterized features of neurodegenerative disorders such as Alzheimer\u2019s disease (AD), the upstream cellular processes driving deficits in pathogenic protein mishandling are less understood. Using a series of fluorescent biosensors and optical imaging in model cells, AD mouse models and human neurons derived from AD patients, we reveal a previously undescribed cellular signaling cascade underlying protein mishandling mediated by intracellular calcium dysregulation, an early component of AD pathogenesis. Increased Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release via the endoplasmic reticulum (ER)-resident ryanodine receptor (RyR) is associated with reduced expression of the lysosome proton pump vacuolar-ATPase (vATPase) subunits (V1B2 and V0a1), resulting in lysosome deacidification and disrupted proteolytic activity in AD mouse models and human-induced neurons (HiN). As a result of impaired lysosome digestive capacity, mature autophagosomes with hyperphosphorylated tau accumulated in AD murine neurons and AD HiN, exacerbating proteinopathy. Normalizing AD-associated aberrant RyR-Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling with the negative allosteric modulator, dantrolene (Ryanodex), restored vATPase levels, lysosomal acidification and proteolytic activity, and autophagic clearance of intracellular protein aggregates in AD neurons. These results highlight that prior to overt AD histopathology or cognitive deficits, aberrant upstream Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling disrupts lysosomal acidification and contributes to pathological accumulation of intracellular protein aggregates. Importantly, this is demonstrated in animal models of AD, and in human iPSC-derived neurons from AD patients. Furthermore, pharmacological suppression of RyR-Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release rescued proteolytic function, revealing a target for therapeutic intervention that has demonstrated effects in clinically-relevant assays.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2211999119","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T17:14:31Z","timestamp":1669655671000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":56,"title":["Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer\u2019s disease"],"prefix":"10.1073","volume":"119","author":[{"given":"Sarah","family":"Mustaly-Kalimi","sequence":"first","affiliation":[{"name":"Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8822-6877","authenticated-orcid":false,"given":"Wacey","family":"Gallegos","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Marr","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8358-3509","authenticated-orcid":false,"given":"Alice","family":"Gilman-Sachs","sequence":"additional","affiliation":[{"name":"Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University of Medicine and Science, Immunology, and Infection, North Chicago, IL 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7275-6403","authenticated-orcid":false,"given":"Daniel A.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7550-1550","authenticated-orcid":false,"given":"Israel","family":"Sekler","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, Faculty of Health Science and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2841-8532","authenticated-orcid":false,"given":"Grace E.","family":"Stutzmann","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,11,28]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2006.07.003"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05291"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1599207"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0800-08.2008"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1100356"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2745"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1174447"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3232"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12169"},{"key":"e_1_3_4_10_2","first-page":"ars.2017.7266","article-title":"Calcium signaling deficits in glia and autophagic pathways contributing to neurodegenerative disease","volume":"29","author":"Mustaly S.","year":"2018","unstructured":"S. Mustaly, A. Littlefield, G. E. Stutzmann, Calcium signaling deficits in glia and autophagic pathways contributing to neurodegenerative disease. Antioxid. Redox Signal.\u00a029, ars.2017.7266\u2013ars.2017.7266 (2018).","journal-title":"Antioxid. Redox Signal."},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1247\/csf.23.33"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2272"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2015.08.005"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.00791"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e11-02-0155"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.05.008"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14612"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-199602290-00029"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5324.373"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0608332104"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200505082"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.07.050"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.409250"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20130201"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2014.01.001"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0197-4580(87)90073-X"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn960"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2005.06.020"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.11.028"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-010-0371-4"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0739-06.2006"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2047-09.2009"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0307-7"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-8-S1-P54"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052056"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0875-12.2012"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2012.04.008"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2015.03.006"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.064"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24713-5"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00089"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-49970-9"},{"key":"e_1_3_4_43_2","doi-asserted-by":"crossref","unstructured":"E. Im Lysosomal dysfunction in Down Syndrome and Alzheimer mouse models is caused by selective v-ATPase inhibition by Tyr682 phosphorylated APP \u03b2CTF. bioRxiv\u00a0[Preprint] (2022). \u00a0https:\/\/doi.org\/10.1101\/2022.06.02.494546. Accessed 6 October 2022.","DOI":"10.1101\/2022.06.02.494546"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000003224"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M000040200"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4386-03.2004"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2474-10.2010"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1733-7"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah5324"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108169"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.39.24234"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.118.1.33"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21031030"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjt022"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.11.013"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.09.029"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.625348"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1701078114"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2020.118800"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2020.02.021"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508211200"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.4161\/cib.27595"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021014-071649"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201510019"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.16-19-06056.1996"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201106120"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201412046"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109034"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl107"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-013-8576-6"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/64.2.113"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2016.1239003"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2017.03.011"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01084-8"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1698-21.2021"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-9-21"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2014.3049"},{"key":"e_1_3_4_78_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002256"},{"key":"e_1_3_4_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.06.073"},{"key":"e_1_3_4_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.11.002"},{"key":"e_1_3_4_81_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0323-7"},{"key":"e_1_3_4_82_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1994.62041337.x"},{"key":"e_1_3_4_83_2","doi-asserted-by":"publisher","DOI":"10.1177\/1073858407299730"},{"key":"e_1_3_4_84_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2008.06.005"},{"key":"e_1_3_4_85_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4805-10.2011"},{"key":"e_1_3_4_86_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.386"},{"key":"e_1_3_4_87_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00038.2015"},{"key":"e_1_3_4_88_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7277"},{"key":"e_1_3_4_89_2","doi-asserted-by":"publisher","DOI":"10.4067\/S0716-97602004000400007"},{"key":"e_1_3_4_90_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00434-3"},{"key":"e_1_3_4_91_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2014.05.013"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2211999119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T08:39:51Z","timestamp":1695285591000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2211999119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,28]]},"references-count":91,"journal-issue":{"issue":"49","published-print":{"date-parts":[[2022,12,6]]}},"alternative-id":["10.1073\/pnas.2211999119"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2211999119","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.08.24.505157","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,28]]},"assertion":[{"value":"2022-07-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2211999119"}}