{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T10:45:40Z","timestamp":1780397140526,"version":"3.54.1"},"reference-count":194,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T00:00:00Z","timestamp":1655510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bijzonder Onderzoeks Fonds KU Leuven","award":["C14\/19\/099"],"award-info":[{"award-number":["C14\/19\/099"]}]},{"name":"Bijzonder Onderzoeks Fonds KU Leuven","award":["G0E7520N"],"award-info":[{"award-number":["G0E7520N"]}]},{"name":"Bijzonder Onderzoeks Fonds KU Leuven","award":["G081821N"],"award-info":[{"award-number":["G081821N"]}]},{"name":"Bijzonder Onderzoeks Fonds KU Leuven","award":["11K7122N"],"award-info":[{"award-number":["11K7122N"]}]},{"name":"Bijzonder Onderzoeks Fonds KU Leuven","award":["SAO IP3 receptor"],"award-info":[{"award-number":["SAO IP3 receptor"]}]},{"name":"Bijzonder Onderzoeks Fonds KU Leuven","award":["2020-J1160630-214966"],"award-info":[{"award-number":["2020-J1160630-214966"]}]},{"name":"Research Foundation\u2014Flanders","award":["C14\/19\/099"],"award-info":[{"award-number":["C14\/19\/099"]}]},{"name":"Research Foundation\u2014Flanders","award":["G0E7520N"],"award-info":[{"award-number":["G0E7520N"]}]},{"name":"Research Foundation\u2014Flanders","award":["G081821N"],"award-info":[{"award-number":["G081821N"]}]},{"name":"Research Foundation\u2014Flanders","award":["11K7122N"],"award-info":[{"award-number":["11K7122N"]}]},{"name":"Research Foundation\u2014Flanders","award":["SAO IP3 receptor"],"award-info":[{"award-number":["SAO IP3 receptor"]}]},{"name":"Research Foundation\u2014Flanders","award":["2020-J1160630-214966"],"award-info":[{"award-number":["2020-J1160630-214966"]}]},{"name":"Stichting Alzheimer Onderzoek","award":["C14\/19\/099"],"award-info":[{"award-number":["C14\/19\/099"]}]},{"name":"Stichting Alzheimer Onderzoek","award":["G0E7520N"],"award-info":[{"award-number":["G0E7520N"]}]},{"name":"Stichting Alzheimer Onderzoek","award":["G081821N"],"award-info":[{"award-number":["G081821N"]}]},{"name":"Stichting Alzheimer Onderzoek","award":["11K7122N"],"award-info":[{"award-number":["11K7122N"]}]},{"name":"Stichting Alzheimer Onderzoek","award":["SAO IP3 receptor"],"award-info":[{"award-number":["SAO IP3 receptor"]}]},{"name":"Stichting Alzheimer Onderzoek","award":["2020-J1160630-214966"],"award-info":[{"award-number":["2020-J1160630-214966"]}]},{"name":"Eye Hope Foundation\/Koning Boudewijnstichting","award":["C14\/19\/099"],"award-info":[{"award-number":["C14\/19\/099"]}]},{"name":"Eye Hope Foundation\/Koning Boudewijnstichting","award":["G0E7520N"],"award-info":[{"award-number":["G0E7520N"]}]},{"name":"Eye Hope Foundation\/Koning Boudewijnstichting","award":["G081821N"],"award-info":[{"award-number":["G081821N"]}]},{"name":"Eye Hope Foundation\/Koning Boudewijnstichting","award":["11K7122N"],"award-info":[{"award-number":["11K7122N"]}]},{"name":"Eye Hope Foundation\/Koning Boudewijnstichting","award":["SAO IP3 receptor"],"award-info":[{"award-number":["SAO IP3 receptor"]}]},{"name":"Eye Hope Foundation\/Koning Boudewijnstichting","award":["2020-J1160630-214966"],"award-info":[{"award-number":["2020-J1160630-214966"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Calcium ions (Ca2+) operate as important messengers in the cell, indispensable for signaling the underlying numerous cellular processes in all of the cell types in the human body. In neurons, Ca2+ signaling is crucial for regulating synaptic transmission and for the processes of learning and memory formation. Hence, the dysregulation of intracellular Ca2+ homeostasis results in a broad range of disorders, including cancer and neurodegeneration. A major source for intracellular Ca2+ is the endoplasmic reticulum (ER), which has close contacts with other organelles, including mitochondria. In this review, we focus on the emerging role of Ca2+ signaling at the ER\u2013mitochondrial interface in two different neurodegenerative diseases, namely Alzheimer\u2019s disease and Wolfram syndrome. Both of these diseases share some common hallmarks in the early stages, including alterations in the ER and mitochondrial Ca2+ handling, mitochondrial dysfunction and increased Reactive oxygen species (ROS) production. This indicates that similar mechanisms may underly these two disease pathologies and suggests that both research topics might benefit from complementary research.<\/jats:p>","DOI":"10.3390\/cells11121963","type":"journal-article","created":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T09:51:11Z","timestamp":1655545871000},"page":"1963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Dysregulated Ca2+ Homeostasis as a Central Theme in Neurodegeneration: Lessons from Alzheimer\u2019s Disease and Wolfram Syndrome"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2847-8674","authenticated-orcid":false,"given":"Manon","family":"Callens","sequence":"first","affiliation":[{"name":"KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg, O\/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8703-9009","authenticated-orcid":false,"given":"Jens","family":"Loncke","sequence":"additional","affiliation":[{"name":"KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg, O\/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5968-4828","authenticated-orcid":false,"given":"Geert","family":"Bultynck","sequence":"additional","affiliation":[{"name":"KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg, O\/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/35036035","article-title":"The versatility and universality of calcium signalling","volume":"1","author":"Berridge","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a038802","DOI":"10.1101\/cshperspect.a038802","article-title":"Fundamentals of Cellular Calcium Signaling: A Primer","volume":"12","author":"Bootman","year":"2020","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/nrm3412","article-title":"Mitochondria as sensors and regulators of calcium signalling","volume":"13","author":"Rizzuto","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"eaaz0961","DOI":"10.1126\/scisignal.aaz0961","article-title":"Full focus on calcium","volume":"12","author":"Parys","year":"2019","journal-title":"Sci. Signal."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1007\/s00018-013-1550-7","article-title":"Neuronal calcium signaling: Function and dysfunction","volume":"71","author":"Brini","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-3-030-12457-1_10","article-title":"New Insights in the IP3 Receptor and Its Regulation","volume":"1131","author":"Parys","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1152\/physrev.00033.2020","article-title":"Calcium-release channels: Structure and function of IP3 receptors and ryanodine receptors","volume":"102","author":"Woll","year":"2022","journal-title":"Physiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"a003996","DOI":"10.1101\/cshperspect.a003996","article-title":"Ryanodine receptors: Structure, expression, molecular details, and function in calcium release","volume":"2","author":"Lanner","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"ra56","DOI":"10.1126\/scisignal.2003649","article-title":"Regulators of calcium homeostasis identified by inference of kinetic model parameters from live single cells perturbed by siRNA","volume":"6","author":"Bandara","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"119020","DOI":"10.1016\/j.bbamcr.2021.119020","article-title":"A comprehensive overview of the complex world of the endo- and sarcoplasmic reticulum Ca2+-leak channels","volume":"1868","author":"Lemos","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.cell.2006.06.059","article-title":"Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer\u2019s disease-linked mutations","volume":"126","author":"Tu","year":"2006","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.cell.2016.04.051","article-title":"TMCO1 Is an ER Ca2+ Load-Activated Ca2+Channel","volume":"165","author":"Wang","year":"2016","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"a035113","DOI":"10.1101\/cshperspect.a035113","article-title":"Primary Active Ca2+ Transport Systems in Health and Disease","volume":"12","author":"Chen","year":"2020","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"a035055","DOI":"10.1101\/cshperspect.a035055","article-title":"Store-Operated Calcium Channels: From Function to Structure and Back Again","volume":"12","author":"Lewis","year":"2020","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"109322","DOI":"10.1016\/j.celrep.2021.109322","article-title":"Orai channel C-terminal peptides are key modulators of STIM-Orai coupling and calcium signal generation","volume":"35","author":"Baraniak","year":"2021","journal-title":"Cell Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108760","DOI":"10.1016\/j.celrep.2021.108760","article-title":"Omnitemporal choreographies of all five STIM\/Orai and IP3Rs underlie the complexity of mammalian Ca2+ signaling","volume":"34","author":"Emrich","year":"2021","journal-title":"Cell Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e2114928118","DOI":"10.1073\/pnas.2114928118","article-title":"Functional communication between IP3R and STIM2 at subthreshold stimuli is a critical checkpoint for initiation of SOCE","volume":"119","author":"Ahmad","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"a004168","DOI":"10.1101\/cshperspect.a004168","article-title":"The plasma membrane Ca2+ ATPase and the plasma membrane sodium calcium exchanger cooperate in the regulation of cell calcium","volume":"3","author":"Brini","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1124\/mol.66.2.276","article-title":"The N-terminal Ca2+-independent calmodulin-binding site on the inositol 1,4,5-trisphosphate receptor is responsible for calmodulin inhibition, even though this inhibition requires Ca2+","volume":"66","author":"Kasri","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S1570-9639(02)00440-5","article-title":"The role of calmodulin for inositol 1,4,5-trisphosphate receptor function","volume":"1600","author":"Bultynck","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"a035543","DOI":"10.1101\/cshperspect.a035543","article-title":"Cytosolic Ca2+ Buffers Are Inherently Ca2+ Signal Modulators","volume":"12","author":"Schwaller","year":"2020","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/978-3-030-12457-1_8","article-title":"An Update to Calcium Binding Proteins","volume":"1131","author":"Elies","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1016\/j.bbamcr.2014.10.029","article-title":"Sense and specificity in neuronal calcium signalling","volume":"1853","author":"Burgoyne","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/sj.emboj.7600037","article-title":"Regulation of InsP3 receptor activity by neuronal Ca2+-binding proteins","volume":"23","author":"Kasri","year":"2004","journal-title":"EMBO J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3622","DOI":"10.1111\/j.1742-4658.2010.07754.x","article-title":"Calcium-dependent mitochondrial function and dysfunction in neurons","volume":"277","author":"Pivovarova","year":"2010","journal-title":"FEBS J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.semcdb.2019.01.009","article-title":"Functional properties and mode of regulation of the mitochondrial Na++\/Ca2+ exchanger, NCLX","volume":"94","author":"Kostic","year":"2019","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102345","DOI":"10.1016\/j.ceca.2020.102345","article-title":"Recent studies on NCLX in health and diseases","volume":"94","author":"Katoshevski","year":"2021","journal-title":"Cell Calcium"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.tcb.2021.02.003","article-title":"Balancing ER-Mitochondrial Ca2+ Fluxes in Health and Disease","volume":"31","author":"Loncke","year":"2021","journal-title":"Trends Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1083\/jcb.200604016","article-title":"Structural and functional features and significance of the physical linkage between ER and mitochondria","volume":"174","author":"Csordas","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1126\/science.280.5370.1763","article-title":"Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses","volume":"280","author":"Rizzuto","year":"1998","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1083\/jcb.200608073","article-title":"Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels","volume":"175","author":"Szabadkai","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.cell.2010.06.007","article-title":"Essential Regulation of Cell Bioenergetics by Constitutive InsP3 Receptor Ca2+ Transfer to Mitochondria","volume":"142","author":"Miller","year":"2010","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.cub.2017.12.047","article-title":"TOM70 Sustains Cell Bioenergetics by Promoting IP3R3-Mediated ER to Mitochondria Ca2+ Transfer","volume":"28","author":"Filadi","year":"2018","journal-title":"Curr. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1161\/CIRCULATIONAHA.117.030235","article-title":"Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo","volume":"136","author":"Wu","year":"2017","journal-title":"Circulation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/s41556-019-0329-y","article-title":"Non-canonical function of IRE1\u03b1 determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics","volume":"21","author":"Urra","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3726","DOI":"10.1038\/s41467-019-11646-3","article-title":"IP3 receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer","volume":"10","author":"Bartok","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.ceca.2011.04.001","article-title":"A dual role for Ca2+ in autophagy regulation","volume":"50","author":"Decuypere","year":"2011","journal-title":"Cell Calcium"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/s41580-018-0052-8","article-title":"The machineries, regulation and cellular functions of mitochondrial calcium","volume":"19","author":"Giorgi","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ceca.2017.05.004","article-title":"Calcium and regulation of the mitochondrial permeability transition","volume":"70","author":"Giorgio","year":"2018","journal-title":"Cell Calcium"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1038\/cdd.2014.84","article-title":"Mitochondrial Ca2+influx targets cardiolipin to disintegrate respiratory chain complex II for cell death induction","volume":"21","author":"Hwang","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.3233\/JAD-160726","article-title":"Mitochondrial Aspects of Synaptic Dysfunction in Alzheimer\u2019s Disease","volume":"57","author":"Cai","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.cell.2007.08.036","article-title":"Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca2+ Signaling and Cell Survival","volume":"131","author":"Hayashi","year":"2007","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1089\/ars.2011.4004","article-title":"Ero1alpha regulates Ca2+ fluxes at the endoplasmic reticulum-mitochondria interface (MAM)","volume":"16","author":"Anelli","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.molcel.2016.05.040","article-title":"Redox Nanodomains Are Induced by and Control Calcium Signaling at the ER-Mitochondrial Interface","volume":"63","author":"Booth","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3866","DOI":"10.1016\/j.molcel.2021.07.014","article-title":"Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER","volume":"81","author":"Booth","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"17464","DOI":"10.1074\/jbc.RA118.005624","article-title":"Redox regulation of type-I inositol trisphosphate receptors in intact mammalian cells","volume":"293","author":"Joseph","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3180","DOI":"10.1016\/j.celrep.2018.11.064","article-title":"IP3 Receptors Preferentially Associate with ER-Lysosome Contact Sites and Selectively Deliver Ca2+ to Lysosomes","volume":"25","author":"Atakpa","year":"2018","journal-title":"Cell Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1042\/BJ20110949","article-title":"Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease","volume":"439","author":"Morgan","year":"2011","journal-title":"Biochem. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ceca.2014.09.010","article-title":"A primer of NAADP-mediated Ca Ca2+ signalling: From sea urchin eggs to mammalian cells","volume":"58","author":"Galione","year":"2015","journal-title":"Cell Calcium"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"eabd5605","DOI":"10.1126\/scisignal.abd5605","article-title":"Essential requirement for JPT2 in NAADP-evoked Ca Ca2+ signaling","volume":"14","author":"Gunaratne","year":"2021","journal-title":"Sci. Signal."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4739","DOI":"10.1038\/s41467-021-24735-z","article-title":"Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles","volume":"12","author":"Zhang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.tibs.2021.10.008","article-title":"NAADP-binding proteins find their identity","volume":"47","author":"Marchant","year":"2022","journal-title":"Trends Biochem. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"102543","DOI":"10.1016\/j.ceca.2022.102543","article-title":"Activation of endo-lysosomal two-pore channels by NAADP and PI(3,5)P2. Five things to know","volume":"103","author":"Patel","year":"2022","journal-title":"Cell Calcium"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"eabe3800","DOI":"10.1126\/scisignal.abe3800","article-title":"Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca Ca2+ signaling during T cell activation","volume":"14","author":"Gu","year":"2021","journal-title":"Sci. Signal."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Serge Gauthier, P.R.-N., Jos\u00e9, A., and Morais, C.W. (2022, March 03). World Alzheimer Report 2021: Journey through the Diagnosis of Dementia. Available online: https:\/\/www.alzint.org\/u\/World-Alzheimer-Report-2021.pdf.","DOI":"10.1016\/j.jns.2023.121394"},{"key":"ref_56","unstructured":"Kumar, A., Sidhu, J., Goyal, A., and Tsao, J.W. (2022). Alzheimer Disease. StatPearls, StatPearls Publishing."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"311","DOI":"10.3233\/JAD-2010-1221","article-title":"Alzheimer\u2019s disease and the amyloid-beta peptide","volume":"19","author":"Murphy","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1056\/NEJM2003ra020003","article-title":"Alzheimer\u2019s Disease and Parkinson\u2019s Disease","volume":"348","author":"Nussbaum","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1016\/j.cell.2021.03.058","article-title":"Alzheimer\u2019s-causing mutations shift Abeta length by destabilizing gamma-secretase-Abetan interactions","volume":"184","author":"Szaruga","year":"2021","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1111\/j.1471-4159.2009.06537.x","article-title":"Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders","volume":"112","author":"Tichauer","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1177\/1073858403252227","article-title":"Amyloid, presenilins, and Alzheimer\u2019s disease","volume":"9","author":"Annaert","year":"2003","journal-title":"Neuroscientist"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/ajmg.1320540319","article-title":"Association of apolipoprotein E allele epsilon 4 with late-onset sporadic Alzheimer\u2019s disease","volume":"54","author":"Lucotte","year":"1994","journal-title":"Am. J. Med. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S1474-4422(18)30053-X","article-title":"The effect of APOE and other common genetic variants on the onset of Alzheimer\u2019s disease and dementia: A community-based cohort study","volume":"17","author":"Wolters","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.ejmech.2018.02.035","article-title":"Secretase inhibitors for the treatment of Alzheimer\u2019s disease: Long road ahead","volume":"148","author":"Kumar","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e14781","DOI":"10.15252\/emmm.202114781","article-title":"Aducanumab: A new phase in therapeutic development for Alzheimer\u2019s disease?","volume":"13","author":"Lalli","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e13037","DOI":"10.1111\/acel.13037","article-title":"Lifelong choline supplementation ameliorates Alzheimer\u2019s disease pathology and associated cognitive deficits by attenuating microglia activation","volume":"18","author":"Velazquez","year":"2019","journal-title":"Aging Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"136528","DOI":"10.1016\/j.neulet.2022.136528","article-title":"Activation of the sigma-1 receptor attenuates blood-brain barrier disruption by inhibiting amyloid deposition in Alzheimer\u2019s disease mice","volume":"774","author":"An","year":"2022","journal-title":"Neurosci. Lett."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: The amyloid cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"926","DOI":"10.2174\/1570159X15666170116143743","article-title":"The Amyloid Cascade Hypothesis in Alzheimer\u2019s Disease: It\u2019s Time to Change Our Mind","volume":"15","author":"Ricciarelli","year":"2017","journal-title":"Curr. Neuropharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1001\/archneur.65.11.1509","article-title":"Frequent amyloid deposition without significant cognitive impairment among the elderly","volume":"65","author":"Aizenstein","year":"2008","journal-title":"Arch. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/ana.22248","article-title":"Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease","volume":"69","author":"Villemagne","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.neurobiolaging.2009.04.002","article-title":"Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease","volume":"30","author":"Price","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_74","first-page":"135","article-title":"Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer\u2019s Disease","volume":"2","author":"Morris","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.1994.tb44398.x","article-title":"Calcium hypothesis of Alzheimer\u2019s disease and brain aging","volume":"747","author":"Khachaturian","year":"1994","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00424-009-0736-1","article-title":"Calcium hypothesis of Alzheimer\u2019s disease","volume":"459","author":"Berridge","year":"2010","journal-title":"Pflug. Arch."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"McDaid, J., Mustaly-Kalimi, S., and Stutzmann, G.E. (2020). Ca2+ Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer\u2019s Disease. Cells, 9.","DOI":"10.3390\/cells9122655"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"344","DOI":"10.2174\/1567205017666200528162046","article-title":"Reversal of Calcium Dysregulation as Potential Approach for Treating Alzheimer\u2019s Disease","volume":"17","author":"Popugaeva","year":"2020","journal-title":"Curr. Alzheimer Res."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association Calcium Hypothesis Workgroup (2017). Calcium Hypothesis of Alzheimer\u2019s disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimer\u2019s Dement., 13, 178\u2013182.e117.","DOI":"10.1016\/j.jalz.2016.12.006"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1007\/s11064-010-0371-4","article-title":"Calcium signalling and Alzheimer\u2019s disease","volume":"36","author":"Berridge","year":"2011","journal-title":"Neurochem. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.ceca.2016.06.008","article-title":"When, where and how? Focus on neuronal calcium dysfunctions in Alzheimer\u2019s Disease","volume":"60","author":"Agostini","year":"2016","journal-title":"Cell Calcium"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"a035212","DOI":"10.1101\/cshperspect.a035212","article-title":"Calcium-Handling Defects and Neurodegenerative Disease","volume":"12","author":"Schrank","year":"2020","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/j.cell.2008.05.048","article-title":"A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer\u2019s disease risk","volume":"133","author":"Lambert","year":"2008","journal-title":"Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.neuron.2008.07.013","article-title":"Linking calcium to Abeta and Alzheimer\u2019s disease","volume":"59","author":"Green","year":"2008","journal-title":"Neuron"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"E1963","DOI":"10.1073\/pnas.1204023109","article-title":"Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability","volume":"109","author":"Ma","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/s00424-015-1757-6","article-title":"Calcium homeostasis modulator (CALHM) ion channels","volume":"468","author":"Ma","year":"2016","journal-title":"Pflug. Arch."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.neuron.2008.06.008","article-title":"Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks","volume":"59","author":"Kuchibhotla","year":"2008","journal-title":"Neuron"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/j.1471-4159.2007.05135.x","article-title":"Increased intraneuronal resting [Ca2+] in adult Alzheimer\u2019s disease mice","volume":"105","author":"Lopez","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.neuron.2008.04.015","article-title":"Mechanism of Ca2+ Disruption in Alzheimer\u2019s Disease by Presenilin Regulation of InsP3 Receptor Channel Gating","volume":"58","author":"Cheung","year":"2008","journal-title":"Neuron"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"ra22","DOI":"10.1126\/scisignal.2000818","article-title":"Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer\u2019s disease-linked presenilin mutants in human cells and mouse neurons","volume":"3","author":"Cheung","year":"2010","journal-title":"Sci. Signal."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"57","DOI":"10.33594\/000000005","article-title":"Glycogen Synthase Kinase 3 Beta Controls Presenilin-1-Mediated Endoplasmic Reticulum Ca(2)(+) Leak Directed to Mitochondria in Pancreatic Islets and beta-Cells","volume":"52","author":"Klec","year":"2019","journal-title":"Cell Physiol. Biochem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S1063-5823(10)66011-5","article-title":"Regulation of IP3R Channel Gating by Ca2+ and Ca2+ Binding Proteins","volume":"66","author":"Foskett","year":"2010","journal-title":"Curr. Top. Membr."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1523\/JNEUROSCI.4386-03.2004","article-title":"Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer\u2019s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability","volume":"24","author":"Stutzmann","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3389\/fnmol.2013.00036","article-title":"Alzheimer\u2019s disease-associated peptide Abeta42 mobilizes ER Ca2+ via InsP3R-dependent and -independent mechanisms","volume":"6","author":"Jensen","year":"2013","journal-title":"Front. Mol. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"18195","DOI":"10.1074\/jbc.M000040200","article-title":"Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons","volume":"275","author":"Chan","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1111\/j.1471-4159.2005.03332.x","article-title":"Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer\u2019s disease","volume":"94","author":"Smith","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0306-4522(99)00042-1","article-title":"Alterations in the ryanodine receptor calcium release channel correlate with Alzheimer\u2019s disease neurofibrillary and beta-amyloid pathologies","volume":"92","author":"Kelliher","year":"1999","journal-title":"Neuroscience"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"5180","DOI":"10.1523\/JNEUROSCI.0739-06.2006","article-title":"Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer\u2019s disease mice","volume":"26","author":"Stutzmann","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"9458","DOI":"10.1523\/JNEUROSCI.2047-09.2009","article-title":"Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3xTg-AD mice","volume":"29","author":"Chakroborty","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1074\/jbc.M206769200","article-title":"Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein","volume":"278","author":"Herms","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/S0896-6273(00)00066-0","article-title":"Presenilin-mediated modulation of capacitative calcium entry","volume":"27","author":"Yoo","year":"2000","journal-title":"Neuron"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1083\/jcb.149.4.793","article-title":"Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice","volume":"149","author":"Leissring","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/0304-3940(96)12696-3","article-title":"Alteration of acylphosphatase levels in familial Alzheimer\u2019s disease fibroblasts with presenilin gene mutations","volume":"210","author":"Liguri","year":"1996","journal-title":"Neurosci. Lett."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1083\/jcb.200706171","article-title":"SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production","volume":"181","author":"Green","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/nrn960","article-title":"Calcium dyshomeostasis and intracellular signalling in Alzheimer\u2019s disease","volume":"3","author":"LaFerla","year":"2002","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"4550","DOI":"10.1021\/bi00181a016","article-title":"Calcium Ionophore Increases Amyloid \u03b2 Peptide Production by Cultured Cells","volume":"33","author":"Querfurth","year":"1994","journal-title":"Biochemistry"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"118998","DOI":"10.1016\/j.bbamcr.2021.118998","article-title":"In vivo brain imaging of mitochondrial Ca2+ in neurodegenerative diseases with multiphoton microscopy","volume":"1868","author":"Kharitonova","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"14670","DOI":"10.1073\/pnas.0903563106","article-title":"Mitochondrial bioenergetic deficit precedes Alzheimer\u2019s pathology in female mouse model of Alzheimer\u2019s disease","volume":"106","author":"Yao","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1016\/j.ajpath.2011.07.004","article-title":"Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer\u2019s disease brain","volume":"179","author":"Kopeikina","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.mito.2007.06.001","article-title":"Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer\u2019s disease","volume":"7","author":"Atamna","year":"2007","journal-title":"Mitochondrion"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"17042","DOI":"10.1523\/JNEUROSCI.1836-13.2013","article-title":"Mitochondrial alterations near amyloid plaques in an Alzheimer\u2019s disease mouse model","volume":"33","author":"Xie","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_112","first-page":"136","article-title":"Mitochondria and Calcium in Alzheimer\u2019s Disease: From Cell Signaling to Neuronal Cell Death","volume":"44","author":"Bacskai","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"13145","DOI":"10.1073\/pnas.0806192105","article-title":"The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae","volume":"105","author":"Alikhani","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1038\/s41467-020-16074-2","article-title":"Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer\u2019s disease","volume":"11","author":"Hou","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ceca.2012.04.015","article-title":"Mitochondrial Ca2+ and neurodegeneration","volume":"52","author":"Cali","year":"2012","journal-title":"Cell Calcium"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1073\/pnas.90.2.567","article-title":"Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: Blockade by tromethamine and aluminum","volume":"90","author":"Arispe","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/S0196-9781(02)00067-0","article-title":"The channel hypothesis of Alzheimer\u2019s disease: Current status","volume":"23","author":"Kagan","year":"2002","journal-title":"Peptides"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nature10234","article-title":"Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter","volume":"476","author":"Baughman","year":"2011","journal-title":"Nature"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1017\/neu.2019.39","article-title":"Mitochondrial calcium uniporter as a potential therapeutic strategy for Alzheimer\u2019s disease","volume":"32","author":"Venugopal","year":"2020","journal-title":"Acta Neuropsychiatr."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Bell, S.M., Barnes, K., De Marco, M., Shaw, P.J., Ferraiuolo, L., Blackburn, D.J., Venneri, A., and Mortiboys, H. (2021). Mitochondrial Dysfunction in Alzheimer\u2019s Disease: A Biomarker of the Future?. Biomedicines, 9.","DOI":"10.3390\/biomedicines9010063"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3885","DOI":"10.1038\/s41467-019-11813-6","article-title":"Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer\u2019s disease","volume":"10","author":"Jadiya","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"102150","DOI":"10.1016\/j.ceca.2019.102150","article-title":"Tau inhibits mitochondrial calcium efflux and makes neurons vulnerable to calcium-induced cell death","volume":"86","author":"Britti","year":"2020","journal-title":"Cell Calcium"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.0959-9673.2005.00427.x","article-title":"Mitochondrial dysfunction and Alzheimer\u2019s disease: Role of amyloid-beta peptide alcohol dehydrogenase (ABAD)","volume":"86","author":"Yan","year":"2005","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1126\/science.1091230","article-title":"ABAD directly links Abeta to mitochondrial toxicity in Alzheimer\u2019s disease","volume":"304","author":"Lustbader","year":"2004","journal-title":"Science"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Fernandes, T., Resende, R., Silva, D.F., Marques, A.P., Santos, A.E., Cardoso, S.M., Domingues, M.R., Moreira, P.I., and Pereira, C.F. (2021). Structural and Functional Alterations in Mitochondria-Associated Membranes (MAMs) and in Mitochondria Activate Stress Response Mechanisms in an In Vitro Model of Alzheimer\u2019s Disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9080881"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.2353\/ajpath.2009.090219","article-title":"Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria","volume":"175","author":"Boldogh","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"4106","DOI":"10.1038\/emboj.2012.202","article-title":"Upregulated function of mitochondria-associated ER membranes in Alzheimer disease","volume":"31","author":"Tambini","year":"2012","journal-title":"EMBO J."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"7916","DOI":"10.1073\/pnas.1300677110","article-title":"Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer\u2019s disease and related models","volume":"110","author":"Hedskog","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"3356","DOI":"10.15252\/embj.201796797","article-title":"Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease","volume":"36","author":"Pera","year":"2017","journal-title":"EMBO J."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s00401-020-02234-7","article-title":"Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer\u2019s disease models and human brains","volume":"141","author":"Mary","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"16243","DOI":"10.1523\/JNEUROSCI.2775-12.2012","article-title":"The beta-secretase-derived C-terminal fragment of betaAPP, C99, but not Abeta, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus","volume":"32","author":"Lauritzen","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_132","first-page":"715","article-title":"Diabetes Mellitus and Simple Optic Atrophy among Siblings: Report on Four Cases","volume":"13","author":"Wolfram","year":"1938","journal-title":"Mayo Clin. Proc."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/s41419-018-0406-3","article-title":"Wolfram syndrome: MAMs\u2019 connection?","volume":"9","author":"Delprat","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s11892-015-0702-6","article-title":"Wolfram Syndrome: Diagnosis, Management, and Treatment","volume":"16","author":"Urano","year":"2016","journal-title":"Curr. Diabetes Rep."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.cophys.2020.07.009","article-title":"Wolfram Syndrome: A Monogenic Model to Study Diabetes Mellitus and Neurodegeneration","volume":"17","author":"Fischer","year":"2020","journal-title":"Curr. Opin. Physiol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1097\/MOP.0b013e328354ccdf","article-title":"Wolfram syndrome 1 and Wolfram syndrome 2","volume":"24","author":"Rigoli","year":"2012","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/pr.2018.17","article-title":"Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease","volume":"83","author":"Rigoli","year":"2018","journal-title":"Pediatr. Res."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.ijdevneu.2014.03.009","article-title":"Initiation and developmental dynamics of Wfs1 expression in the context of neural differentiation and ER stress in mouse forebrain","volume":"35","author":"Tekko","year":"2014","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1530\/eje.1.01945","article-title":"Endoplasmic reticulum stress induces Wfs1 gene expression in pancreatic beta-cells via transcriptional activation","volume":"153","author":"Ueda","year":"2005","journal-title":"Eur. J. Endocrinol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1097\/WNR.0000000000000624","article-title":"Expression pattern of wolframin, the WFS1 (Wolfram syndrome-1 gene) product, in common marmoset (Callithrix jacchus) cochlea","volume":"27","author":"Suzuki","year":"2016","journal-title":"Neuroreport"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1093\/hmg\/ddl081","article-title":"WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells","volume":"15","author":"Yamada","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"39609","DOI":"10.1074\/jbc.M507426200","article-title":"WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells","volume":"280","author":"Fonseca","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Sakakibara, Y., Sekiya, M., Fujisaki, N., Quan, X., and Iijima, K.M. (2018). Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in Drosophila. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007196"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Crouzier, L., Richard, E.M., Diez, C., Alzaeem, H., Denus, M., Cubedo, N., Delaunay, T., Glendenning, E., Baxendale, S., and Li\u00e9vens, J.-C. (2022). Morphological, behavioral and cellular analyses revealed different phenotypes in Wolfram syndrome wfs1a and wfs1b zebrafish mutant lines. Hum. Mol. Genet.","DOI":"10.1093\/hmg\/ddac065"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"eabc6165","DOI":"10.1126\/scisignal.abc6165","article-title":"Uniting the divergent Wolfram syndrome-linked proteins WFS1 and CISD2 as modulators of Ca2+ signaling","volume":"14","author":"Loncke","year":"2021","journal-title":"Sci. Signal."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"4770","DOI":"10.1093\/hmg\/ddu193","article-title":"Cisd2 modulates the differentiation and functioning of adipocytes by regulating intracellular Ca2+ homeostasis","volume":"23","author":"Wang","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"118805","DOI":"10.1016\/j.bbamcr.2020.118805","article-title":"The balancing act of NEET proteins: Iron, ROS, calcium and metabolism","volume":"1867","author":"Nechushtai","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Karmi, O., Holt, S.H., Song, L., Tamir, S., Luo, Y., Bai, F., Adenwalla, A., Darash-Yahana, M., Sohn, Y.S., and Jennings, P.A. (2017). Interactions between mitoNEET and NAF-1 in cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0175796"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"118954","DOI":"10.1016\/j.bbamcr.2021.118954","article-title":"CISD2 maintains cellular homeostasis","volume":"1868","author":"Shen","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/path.5374","article-title":"Upregulation of Cisd2 attenuates Alzheimer\u2019s-related neuronal loss in mice","volume":"250","author":"Chen","year":"2020","journal-title":"J. Pathol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"103654","DOI":"10.1016\/j.ebiom.2021.103654","article-title":"Cisd2 plays an essential role in corneal epithelial regeneration","volume":"73","author":"Sun","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"103741","DOI":"10.1016\/j.ebiom.2021.103741","article-title":"Keeping an eye on Ca2+ signalling to tackle dry eye diseases","volume":"74","author":"Sneyers","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"52755","DOI":"10.1074\/jbc.M310331200","article-title":"Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium","volume":"278","author":"Osman","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Cagalinec, M., Liiv, M., Hodurova, Z., Hickey, M.A., Vaarmann, A., Mandel, M., Zeb, A., Choubey, V., Kuum, M., and Safiulina, D. (2016). Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome. PLoS Biol., 14.","DOI":"10.1371\/journal.pbio.1002511"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"eaaq1380","DOI":"10.1126\/scisignal.aaq1380","article-title":"ER-mitochondria cross-talk is regulated by the Ca2+ sensor NCS1 and is impaired in Wolfram syndrome","volume":"11","author":"Angebault","year":"2018","journal-title":"Sci. Signal."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1093\/hmg\/ddu499","article-title":"Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression","volume":"24","author":"Zatyka","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"E5292","DOI":"10.1073\/pnas.1421055111","article-title":"A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome","volume":"111","author":"Lu","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"17389","DOI":"10.1073\/pnas.2007136117","article-title":"Calpain inhibitor and ibudilast rescue beta cell functions in a cellular model of Wolfram syndrome","volume":"117","author":"Nguyen","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.1016\/j.febslet.2006.09.007","article-title":"WFS1 protein modulates the free Ca2+ concentration in the endoplasmic reticulum","volume":"580","author":"Takei","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_160","first-page":"e145188","article-title":"A phase Ib\/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome","volume":"6","author":"Abreu","year":"2021","journal-title":"JCI Insight"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1093\/hmg\/ddx060","article-title":"A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions","volume":"26","author":"Rouzier","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Yeh, C.H., Shen, Z.Q., Hsiung, S.Y., Wu, P.C., Teng, Y.C., Chou, Y.J., Fang, S.W., Chen, C.F., Yan, Y.T., and Kao, L.S. (2019). Cisd2 is essential to delaying cardiac aging and to maintaining heart functions. PLoS Biol., 17.","DOI":"10.1371\/journal.pbio.3000508"},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Huang, Y.L., Shen, Z.Q., Huang, C.H., Teng, Y.C., Lin, C.H., and Tsai, T.F. (2021). Cisd2 Protects the Liver from Oxidative Stress and Ameliorates Western Diet-Induced Nonalcoholic Fatty Liver Disease. Antioxidants, 10.","DOI":"10.3390\/antiox10040559"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1093\/hmg\/dds048","article-title":"Bcl-2-associated autophagy regulator Naf-1 required for maintenance of skeletal muscle","volume":"21","author":"Chang","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/emboj.2009.369","article-title":"Antagonism of Beclin 1-dependent autophagy by BCL-2 at the endoplasmic reticulum requires NAF-1","volume":"29","author":"Chang","year":"2010","journal-title":"EMBO J."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"a035089","DOI":"10.1101\/cshperspect.a035089","article-title":"Bcl-2-protein family as modulators of IP3 receptors and other organellar Ca2+ channels","volume":"12","author":"Ivanova","year":"2020","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"5177","DOI":"10.1073\/pnas.1403770111","article-title":"Integrated strategy reveals the protein interface between cancer targets Bcl-2 and NAF-1","volume":"111","author":"Tamir","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"14397","DOI":"10.1073\/pnas.0907555106","article-title":"The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor","volume":"106","author":"Rong","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"118983","DOI":"10.1016\/j.bbamcr.2021.118983","article-title":"Cancer cell death strategies by targeting Bcl-2\u2019s BH4 domain","volume":"1868","author":"Kerkhofs","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1042\/BJ20040072","article-title":"Thimerosal stimulates Ca2+ flux through inositol 1,4,5-trisphosphate receptor type 1, but not type 3, via modulation of an isoform-specific Ca2+-dependent intramolecular interaction","volume":"381","author":"Bultynck","year":"2004","journal-title":"Biochem. J."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"11893","DOI":"10.1038\/s41598-017-12131-x","article-title":"Upregulation of CISD2 augments ROS homeostasis and contributes to tumorigenesis and poor prognosis of lung adenocarcinoma","volume":"7","author":"Li","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1002\/emmm.201201429","article-title":"Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis","volume":"5","author":"Wiley","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"e13523","DOI":"10.1111\/acel.13523","article-title":"Cisd2 slows down liver aging and attenuates age-related metabolic dysfunction in male mice","volume":"20","author":"Huang","year":"2021","journal-title":"Aging Cell"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1086\/520961","article-title":"A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2","volume":"81","author":"Amr","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"eabh3763","DOI":"10.1126\/scitranslmed.abh3763","article-title":"Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models","volume":"14","author":"Crouzier","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1101\/gad.1779509","article-title":"Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice","volume":"23","author":"Chen","year":"2009","journal-title":"Genes Dev."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.1016\/j.celrep.2017.10.099","article-title":"CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma","volume":"21","author":"Shen","year":"2017","journal-title":"Cell Rep."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"3592","DOI":"10.1210\/jc.2016-2240","article-title":"GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves beta-Cell Function in Type 2 Wolfram Syndrome","volume":"101","author":"Danielpur","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1242\/jcs.178293","article-title":"Activation of apoptosis in NAF-1-deficient human epithelial breast cancer cells","volume":"129","author":"Holt","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1172\/JCI39678","article-title":"Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells","volume":"120","author":"Fonseca","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Bonnet Wersinger, D., Benkafadar, N., Jagodzinska, J., Hamel, C., Tanizawa, Y., Lenaers, G., and Delettre, C. (2014). Impairment of visual function and retinal ER stress activation in Wfs1-deficient mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097222"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"e989","DOI":"10.1038\/cddis.2013.522","article-title":"JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death","volume":"5","author":"Win","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1111\/j.1755-5949.2010.00177.x","article-title":"The role of tau in Alzheimer\u2019s disease and related disorders","volume":"17","author":"Medeiros","year":"2011","journal-title":"CNS Neurosci. Ther."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1007\/s00401-022-02417-4","article-title":"Wolframin is a novel regulator of tau pathology and neurodegeneration","volume":"143","author":"Chen","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"11820","DOI":"10.1523\/JNEUROSCI.0875-12.2012","article-title":"Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease","volume":"32","author":"Oules","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s00401-017-1733-7","article-title":"Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer\u2019s disease-like pathologies and cognitive deficits","volume":"134","author":"Lacampagne","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_187","doi-asserted-by":"crossref","unstructured":"Yao, J., Liu, Y., Sun, B., Zhan, X., Estillore, J.P., Turner, R.W., and Chen, S.R.W. (2022). Increased RyR2 open probability induces neuronal hyperactivity and memory loss with or without Alzheimer\u2019s disease-causing gene mutations. Alzheimer\u2019s Dement.","DOI":"10.1002\/alz.12543"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jphs.2020.06.007","article-title":"TLR4-TAK1-p38 MAPK pathway and HDAC6 regulate the expression of sigma-1 receptors in rat primary cultured microglia","volume":"144","author":"Iwamoto","year":"2020","journal-title":"J. Pharmacol. Sci."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1093\/hmg\/ddt008","article-title":"Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis","volume":"22","author":"Prause","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1600-0404.2005.00432.x","article-title":"Function of sigma1 receptors in Parkinson\u2019s disease","volume":"112","author":"Mishina","year":"2005","journal-title":"Acta Neurol. Scand."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.nbd.2018.12.022","article-title":"Pridopidine stabilizes mushroom spines in mouse models of Alzheimer\u2019s disease by acting on the sigma-1 receptor","volume":"124","author":"Ryskamp","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"118997","DOI":"10.1016\/j.bbamcr.2021.118997","article-title":"The role of Bcl-2 proteins in modulating neuronal Ca2+ signaling in health and in Alzheimer\u2019s disease","volume":"1868","author":"Callens","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1523\/JNEUROSCI.5620-07.2008","article-title":"Lack of pathology in a triple transgenic mouse model of Alzheimer\u2019s disease after overexpression of the anti-apoptotic protein Bcl-2","volume":"28","author":"Rohn","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.neubiorev.2020.09.011","article-title":"Function of WFS1 and WFS2 in the Central Nervous System: Implications for Wolfram Syndrome and Alzheimer\u2019s disease","volume":"118","author":"Li","year":"2020","journal-title":"Neurosci. Biobehav. Rev."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/12\/1963\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:34:32Z","timestamp":1760139272000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/12\/1963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,18]]},"references-count":194,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["cells11121963"],"URL":"https:\/\/doi.org\/10.3390\/cells11121963","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,18]]}}}