{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T09:26:35Z","timestamp":1762075595906,"version":"build-2065373602"},"reference-count":64,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T00:00:00Z","timestamp":1669075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Taiwan, ROC","award":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"],"award-info":[{"award-number":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"],"award-info":[{"award-number":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"]}]},{"name":"National Health Research Institute","award":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"],"award-info":[{"award-number":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"]}]},{"DOI":"10.13039\/100000005","name":"Department of Defense USA","doi-asserted-by":"publisher","award":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"],"award-info":[{"award-number":["108-2320-B-006-020","109-2320-B-006-058","110-2320-B-006-056","NHRI-EX107-10734NI","W81XWH-08-1-0682"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>When WWOX is downregulated in middle age, aggregation of a protein cascade, including TRAPPC6A\u0394 (TPC6A\u0394), TIAF1, and SH3GLB2, may start to occur, and the event lasts more than 30 years, which results in amyloid precursor protein (APP) degradation, amyloid beta (A\u03b2) generation, and neurodegeneration, as shown in Alzheimer\u2019s disease (AD). Here, by treating neuroblastoma SK-N-SH cells with neurotoxin MPP+, upregulation and aggregation of TPC6A\u0394, along with aggregation of TIAF1, SH3GLB2, A\u03b2, and tau, occurred. MPP+ is an inducer of Parkinson\u2019s disease (PD), suggesting that TPC6A\u0394 is a common initiator for AD and PD pathogenesis. Zfra, a 31-amino-acid zinc finger-like WWOX-binding protein, is known to restore memory deficits in 9-month-old triple-transgenic (3xTg) mice by blocking the aggregation of TPC6A\u0394, SH3GLB2, tau, and amyloid \u03b2, as well as inflammatory NF-\u03baB activation. The Zfra4-10 peptide exerted a strong potency in preventing memory loss during the aging of 3-month-old 3xTg mice up to 9 months, as determined by a novel object recognition task (ORT) and Morris water maize analysis. Compared to age-matched wild type mice, 11-month-old Wwox heterozygous mice exhibited memory loss, and this correlates with pT12-WWOX aggregation in the cortex. Together, aggregation of pT12-WWOX may link to TPC6A\u0394 aggregation for AD progression, with TPC6A\u0394 aggregation being a common initiator for AD and PD progression.<\/jats:p>","DOI":"10.3390\/ijms232314510","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T08:25:28Z","timestamp":1669105528000},"page":"14510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Zfra Inhibits the TRAPPC6A\u0394-Initiated Pathway of Neurodegeneration"],"prefix":"10.3390","volume":"23","author":[{"given":"Yu-Hao","family":"Lin","sequence":"first","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9145-7492","authenticated-orcid":false,"given":"Yao-Hsiang","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"},{"name":"Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Sanmin District, Kaohsiung 80708, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye Vone","family":"Yap","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen-Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsiang-Lin","family":"Kuo","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsung-Yun","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Jin","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4867-2482","authenticated-orcid":false,"given":"Yu-Min","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6889-8756","authenticated-orcid":false,"given":"Nan-Shan","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"},{"name":"Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Sanmin District, Kaohsiung 80708, Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"},{"name":"Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, New York, NY 10314, USA"},{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404333, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer disease: An update on pathobiology and treatment strategies","volume":"179","author":"Long","year":"2019","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.neuroscience.2020.11.015","article-title":"A multilevel view of the development of Alzheimer\u2019s disease","volume":"457","author":"Avila","year":"2021","journal-title":"Neuroscience"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1255555","DOI":"10.1126\/science.1255555","article-title":"Neurodegeneration. 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