{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:41:09Z","timestamp":1760150469470,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre (Poland)","award":["2013\/09\/D\/NZ3\/01348","2015\/17\/D\/NZ2\/03711"],"award-info":[{"award-number":["2013\/09\/D\/NZ3\/01348","2015\/17\/D\/NZ2\/03711"]}]},{"name":"Foundation for Polish Science","award":["2013\/09\/D\/NZ3\/01348","2015\/17\/D\/NZ2\/03711"],"award-info":[{"award-number":["2013\/09\/D\/NZ3\/01348","2015\/17\/D\/NZ2\/03711"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Presenilin 1 (PS1) forms, via its large cytosolic loop, a trimeric complex with N-cadherin and \u03b2-catenin, which is a key component of Wnt signaling. PS1 undergoes phosphorylation at 353 and 357 serines upon enhanced activity and elevated levels of the GSK3\u03b2 isoform. PS1 mutations surrounding these serines may alter the stability of the \u03b2-catenin complex. Such mutations are found in some cases of familial early-onset Alzheimer\u2019s disease (fEOAD), but their functional impact remains obscure. One of such variants of PS1, the A360T substitution, is located close to GSK3\u03b2-targeted serine residues. This variant was recently demonstrated in the French population, but more detail is needed to understand its biological effects. To assess the significance of this variant, we employed functional studies using a fibroblast cell line from an Alzheimer\u2019s disease case (a female proband) carrying the A360T mutation. Based on functional transcriptomic, cellular, and biochemical assays, we demonstrated atypically impaired \u03b2-catenin\/GSK3\u03b2 signaling in the A360T patient\u2019s fibroblasts. In detail, this was characterized by a decreased level of active cytosolic \u03b2-catenin and bound by PS1, an increased level of nuclear \u03b2-catenin, an increased level of inhibited GSK3\u03b2 phosphorylated on Ser9, and enhanced interaction of GSK3\u03b2(Ser9) with PS1. Based on the transcriptomic profile of the A360T fibroblasts, we proposed a dysregulated transcriptional activity of \u03b2-catenin, exemplified by increased expression of various cyclin-dependent kinases and cyclins, such as cyclin D1, potentially inducing neurons\u2019 cell cycle re-entry followed by apoptosis. The A360T cells did not exhibit significant amyloid pathology. Therefore, cell death in this PS1 cytosolic loop mutation may be attributed to impaired \u03b2-catenin\/GSK3\u03b2 signaling rather than amyloid deposition per se. We further estimated the biological and clinical relevance of the A360T variant by whole exome sequencing (WES). WES was performed on DNA from the blood of an A360T female proband, as well as an unrelated male patient carrying the A360T mutation and his mutation-free daughter (both unavailable for the derivation of the fibroblast cell lines). WES confirmed the highest-priority AD causality of the A360T variant in PS1 and also profiled the pathways and processes involved in the A360T case, highlighting the greatest importance of altered Wnt signaling.<\/jats:p>","DOI":"10.3390\/ijms242316999","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T07:44:42Z","timestamp":1701330282000},"page":"16999","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rare A360T Mutation Alters GSK3\u03b2(Ser9) Binding in the Cytosolic Loop of Presenilin 1, Influencing \u03b2-Catenin Nuclear Localization and Pro-Death Gene Expression in Alzheimer\u2019s Disease Case"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7498-4610","authenticated-orcid":false,"given":"Michalina","family":"W\u0119\u017cyk","sequence":"first","affiliation":[{"name":"Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawi\u0144skiego Street, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2076-4318","authenticated-orcid":false,"given":"Mariusz","family":"Berdy\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawi\u0144skiego Street, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7513-7157","authenticated-orcid":false,"given":"Adam","family":"Figarski","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawi\u0144skiego Street, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Skrzypczak","sequence":"additional","affiliation":[{"name":"Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, 14 Indiry Gandhi Street, 02-776 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7538-1571","authenticated-orcid":false,"given":"Krzysztof","family":"Ginalski","sequence":"additional","affiliation":[{"name":"Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, 93 \u017bwirki i Wigury Street, 02-089 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marzena","family":"Zboch","sequence":"additional","affiliation":[{"name":"Research and Education Center for Dementia Diseases in \u015acinawa, Alzheimer\u2019s Center, 12 Jana Paw\u0142a II Street, 59-330 \u015acinawa, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Izabela","family":"Winkel","sequence":"additional","affiliation":[{"name":"Research and Education Center for Dementia Diseases in \u015acinawa, Alzheimer\u2019s Center, 12 Jana Paw\u0142a II Street, 59-330 \u015acinawa, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7332-8494","authenticated-orcid":false,"given":"Cezary","family":"\u017bekanowski","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawi\u0144skiego Street, 02-106 Warsaw, Poland"},{"name":"Faculty of Physical Education, Gdansk University of Physical Education and Sport, G\u00f3rskiego 1 Street, 80-336 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"10863","DOI":"10.1073\/pnas.191284198","article-title":"Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis","volume":"98","author":"Xia","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.cell.2006.10.018","article-title":"Wnt\/beta-catenin signaling in development and disease","volume":"127","author":"Clevers","year":"2006","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/35096075","article-title":"The renaissance of GSK3","volume":"2","author":"Cohen","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1111\/j.1471-4159.2007.05194.x","article-title":"The GSK3 hypothesis of Alzheimer\u2019s disease","volume":"104","author":"Hooper","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41392-021-00762-6","article-title":"Wnt\/\u03b2-catenin signalling: Function, biological mechanisms, and therapeutic opportunities","volume":"7","author":"Liu","year":"2022","journal-title":"Signal Transduct Target Ther."},{"doi-asserted-by":"crossref","unstructured":"Lanoisel\u00e9e, H.M., Nicolas, G., Wallon, D., Rovelet-Lecrux, A., Lacour, M., Rousseau, S., Richard, A.C., Pasquier, F., Rollin-Sillaire, A., and Martinaud, O. (2017). APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med., 14.","key":"ref_7","DOI":"10.1371\/journal.pmed.1002270"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3233\/JAD-170830","article-title":"Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer\u2019s Disease","volume":"62","author":"Wezyk","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1172\/JCI133737","article-title":"Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease","volume":"130","author":"Roy","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1159\/000051261","article-title":"Synaptosomal proteins, beta-soluble N-ethylmaleimide-sensitive factor attachment protein (beta-SNAP), gamma-SNAP and synaptotagmin I in brain of patients with Down syndrome and Alzheimer\u2019s disease","volume":"12","author":"Yoo","year":"2001","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10248","DOI":"10.1002\/jcb.28309","article-title":"Crosstalk between Phosphoinositide 3-kinase\/Akt signaling pathway with DNA damage response and oxidative stress in cancer","volume":"120","author":"Karimian","year":"2019","journal-title":"J. Cell Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1091\/mbc.e03-01-0865","article-title":"Beta-catenin regulation during the cell cycle: Implications in G2\/M and apoptosis","volume":"14","author":"Olmeda","year":"2003","journal-title":"Mol. Biol. Cell."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.pharmthera.2014.11.016","article-title":"Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases","volume":"148","author":"Beurel","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.brainres.2010.11.032","article-title":"Pharmacological reversal of synaptic plasticity deficits in the mouse model of fragile X syndrome by group II mGluR antagonist or lithium treatment","volume":"1380","author":"Choi","year":"2011","journal-title":"Brain Res."},{"doi-asserted-by":"crossref","unstructured":"Lauretti, E., Dincer, O., and Pratic\u00f2, D. (2020). Glycogen synthase kinase-3 signaling in Alzheimer\u2019s disease. Biochim. Biophys. Acta Mol. Cell Res., 1867.","key":"ref_15","DOI":"10.1016\/j.bbamcr.2020.118664"},{"doi-asserted-by":"crossref","unstructured":"Yang, K., Guo, Y., Stacey, W.C., Harwalkar, J., Fretthold, J., Hitomi, M., and Stacey, D.W. (2006). Glycogen synthase kinase 3 has a limited role in cell cycle regulation of cyclin D1 levels. BMC Cell Biol., 7.","key":"ref_16","DOI":"10.1186\/1471-2121-7-33"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18414","DOI":"10.1074\/jbc.M110.209718","article-title":"Age-dependent accumulation of soluble amyloid beta (Abeta) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-alpha (sAPP(alpha)) by modulating phosphatidylinositol 3-kinase (PI3K)\/Akt-GSK-3beta pathway in Alzheimer mouse model","volume":"286","author":"Jimenez","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.trci.2019.06.008","article-title":"Alzheimer\u2019s disease mechanisms in peripheral cells: Promises and challenges","volume":"5","author":"Trushinaa","year":"2019","journal-title":"Alzheimers Dement."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14083","DOI":"10.1074\/jbc.M608437200","article-title":"A structural switch of presenilin 1 by glycogen synthase kinase 3beta-mediated phosphorylation regulates the interaction with beta-catenin and its nuclear signaling","volume":"282","author":"Prager","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e19720","DOI":"10.7554\/eLife.19720","article-title":"Pathogenic PS1 phosphorylation at Ser367","volume":"6","author":"Maesako","year":"2017","journal-title":"eLife"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.1093\/hmg\/ddy190","article-title":"The presenilin loop region is essential for glycogen synthase kinase 3 \u03b2 (GSK3\u03b2) mediated functions on motor proteins during axonal transport","volume":"27","author":"Banerjee","year":"2018","journal-title":"Hum. Mol. Genet."},{"doi-asserted-by":"crossref","unstructured":"Bonds, J.A., Kuttner-Hirshler, Y., Bartolotti, N., Tobin, M.K., Pizzi, M., Marr, R., and Lazarov, O. (2015). Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory. PLoS ONE, 10.","key":"ref_22","DOI":"10.1371\/journal.pone.0131266"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"36007","DOI":"10.1074\/jbc.M507503200","article-title":"Cadherins mediate both the association between PS1 and beta-catenin and the effects of PS1 on beta-catenin stability","volume":"280","author":"Serban","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_24","first-page":"3519","article-title":"Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice","volume":"119","author":"Huang","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"226","DOI":"10.4161\/cbt.72","article-title":"Cycling to cancer with cyclin D1","volume":"1","author":"Diehl","year":"2002","journal-title":"Cancer Biol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1128\/MCB.16.6.2554","article-title":"Cyclin D1 triggers autonomous growth of breast cancer cells by governing cell cycle exit","volume":"16","author":"Zwijsen","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1101\/gad.8.14.1627","article-title":"Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts","volume":"8","author":"Pagano","year":"1994","journal-title":"Genes Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"33972","DOI":"10.18632\/oncotarget.15687","article-title":"The regulation of \u03b2-catenin activity and function in cancer: Therapeutic opportunities","volume":"8","author":"Shang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4","DOI":"10.12965\/jer.1836054.027","article-title":"Treadmill exercise activates PI3K\/Akt signaling pathway leading to GSK-3\u03b2 inhibition in the social isolated rat pups","volume":"14","author":"Wang","year":"2018","journal-title":"J. Exerc. Rehabil."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.molcel.2011.03.033","article-title":"Phosphorylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53","volume":"42","author":"Charvet","year":"2011","journal-title":"Mol. Cell."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"397","DOI":"10.3233\/JAD-2012-121129","article-title":"Highly pathogenic Alzheimer\u2019s disease presenilin 1 P117R mutation causes a specific increase in p53 and p21 protein levels and cell cycle dysregulation in human lymphocytes","volume":"32","author":"Bialopiotrowicz","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5683","DOI":"10.1007\/s12035-016-0105-y","article-title":"Familial Alzheimer\u2019s Disease Lymphocytes Respond Differently Than Sporadic Cells to Oxidative Stress: Upregulated p53-p21 Signaling Linked with Presenilin 1 Mutants","volume":"54","author":"Wojsiat","year":"2017","journal-title":"Mol. Neurobiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16999\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:35:01Z","timestamp":1760132101000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16999"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,30]]},"references-count":32,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242316999"],"URL":"https:\/\/doi.org\/10.3390\/ijms242316999","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,11,30]]}}}