{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:23:47Z","timestamp":1760145827538,"version":"build-2065373602"},"reference-count":72,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea","award":["2021R1A6A1A03038996","RS-2023-00251396"],"award-info":[{"award-number":["2021R1A6A1A03038996","RS-2023-00251396"]}]},{"name":"Ministry of Education Korea","award":["2021R1A6A1A03038996","RS-2023-00251396"],"award-info":[{"award-number":["2021R1A6A1A03038996","RS-2023-00251396"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In this manuscript, a novel presenilin-2 (PSEN2) mutation, Val226Ala, was found in a 59-year-old Korean patient who exhibited rapid progressive memory dysfunction and hallucinations six months prior to her first visit to the hospital. Her Magnetic Resonance Imaging (MRI) showed brain atrophy, and both amyloid positron emission tomography (PET) and multimer detection system-oligomeric amyloid-beta (A\u03b2) results were positive. The patient was diagnosed with early onset Alzheimer\u2019s disease. The whole-exome analysis revealed a new PSEN2 Val226Ala mutation with heterozygosity in the 5th transmembrane domain of the PSEN2 protein near the lumen region. Analyses of the structural prediction suggested structural changes in the helix, specifically a loss of a hydrogen bond between Val226 and Gln229, which may lead to elevated helix motion. Multiple PSEN2 mutations were reported in PSEN2 transmembrane-5 (TM5), such as Tyr231Cys, Ile235Phe, Ala237Val, Leu238Phe, Leu238Pro, and Met239Thr, highlighting the dynamic importance of the 5th transmembrane domain of PSEN2. Mutations in TM5 may alter the access tunnel of the A\u03b2 substrate in the membrane to the gamma-secretase active site, indicating a possible influence on enzyme function that increases A\u03b2 production. Interestingly, the current patient with the Val226Ala mutation presented with a combination of hallucinations and memory dysfunction. Although the causal mechanisms of hallucinations in AD remain unclear, it is possible that PSEN2 interacts with other disease risk factors, including Notch Receptor 3 (NOTCH3) or Glucosylceramidase Beta-1 (GBA) variants, enhancing the occurrence of hallucinations. In conclusion, the direct or indirect role of PSEN2 Val226Ala in AD onset cannot be ruled out.<\/jats:p>","DOI":"10.3390\/ijms25179678","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T11:53:11Z","timestamp":1725623591000},"page":"9678","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Rare PSEN2 Val226Ala in PSEN2 in a Korean Patient with Atypical Alzheimer\u2019s Disease, and the Importance of PSEN2 5th Transmembrane Domain (TM5) in AD Pathogenesis"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2448-2599","authenticated-orcid":false,"given":"YoungSoon","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurology, Soonchunhyang University College of Medicine, Cheonan Hospital, Cheonan 31151, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Bagyinszky","sequence":"additional","affiliation":[{"name":"Department of Industrial and Environmental Engineering, Gachon University Graduate School of Environment, Gachon University, Seongnam-si 13120, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8123-6183","authenticated-orcid":false,"given":"Seong Soo A.","family":"An","sequence":"additional","affiliation":[{"name":"Department of Bionano Technology, Gachon Medical Research Institute, College of Bionano Technology, Gachon University, Seongnam-si 13120, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3590","DOI":"10.1074\/jbc.272.6.3590","article-title":"Phosphorylation, subcellular localization, and membrane orientation of the Alzheimer\u2019s disease-associated presenilins","volume":"272","author":"Beullens","year":"1997","journal-title":"J. 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