{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:48:48Z","timestamp":1775753328621,"version":"3.50.1"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Neprilysin (NEP) is a major enzyme that degrades amyloid \u03b2-peptide (A\u03b2) in the brain. Deficient NEP activity causes A\u03b2 to accumulate, leading to amyloid pathology in Alzheimer's disease. Transcripts from the MME gene encoding NEP comprise seven splice variants (v1, v1bis, v2a, v2b and v3\u20135) with different structures in the 5\u2032-untranslated region. We analyzed the expression levels of MME variants in neuronal and non-neuronal cells using real-time PCR and investigated their translational outputs using cells co-transfected with cDNAs of each MME variant and green fluorescent protein. v1 and v1bis were constitutively expressed as major components in both cell types, whereas v2b was preferentially expressed in non-neuronal cells. The translational outputs of v1 and v2b were similar to each other and much higher than those of the other variants. Retinoic acid-induced neuronal differentiation altered the compositional ratios of MME variants and transiently enhanced their translational outputs, which declined in a variant-specific manner with further differentiation. We demonstrated that MME variants show cell type-dependent expression and distinct translational outputs that are sensitive to retinoic acid. Further studies are required to elucidate the molecular mechanisms underlying the post-translational roles of MME variants, such as subcellular localization and local translation.<\/jats:p>","DOI":"10.1093\/jb\/mvag002","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T12:41:04Z","timestamp":1767789664000},"page":"269-281","source":"Crossref","is-referenced-by-count":0,"title":["Cell type- and neuronal differentiation-dependent\n                    <i>MME<\/i>\n                    5\u2032UTR splice variants with distinct translational outputs in human cells"],"prefix":"10.1093","volume":"179","author":[{"given":"Shiori","family":"Iwamoto","sequence":"first","affiliation":[{"name":"Department of Genome-based Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7972-1852","authenticated-orcid":false,"given":"Daisuke","family":"Hatta","sequence":"additional","affiliation":[{"name":"Department of Genome-based Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]},{"name":"Leading Medical Research Core Unit, Graduate School of Biomedical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]},{"name":"Faculty of Pharmaceutical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misato","family":"Fujii","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daiki","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Genome-based Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryosuke","family":"Ohta","sequence":"additional","affiliation":[{"name":"Department of Genome-based Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Okita","sequence":"additional","affiliation":[{"name":"Department of Genome-based Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6507-492X","authenticated-orcid":false,"given":"Keiro","family":"Shirotani","sequence":"additional","affiliation":[{"name":"Leading Medical Research Core Unit, Graduate School of Biomedical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]},{"name":"Faculty of Pharmaceutical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8721-7947","authenticated-orcid":false,"given":"Nobuhisa","family":"Iwata","sequence":"additional","affiliation":[{"name":"Department of Genome-based Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]},{"name":"Leading Medical Research Core Unit, Graduate School of Biomedical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]},{"name":"Faculty of Pharmaceutical Sciences, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki-shi, Nagasaki 852-8521 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"2026040911515875400_ref1","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1126\/science.1059946","article-title":"Metabolic regulation of brain A\u03b2 by neprilysin","volume":"292","author":"Iwata","year":"2001","journal-title":"Science."},{"key":"2026040911515875400_ref2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/72237","article-title":"Identification of the major A\u03b21-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition","volume":"6","author":"Iwata","year":"2000","journal-title":"Nat. Med."},{"key":"2026040911515875400_ref3","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.pharmthera.2005.03.010","article-title":"Metabolism of amyloid-\u03b2 peptide and Alzheimer\u2019s disease","volume":"108","author":"Iwata","year":"2005","journal-title":"Pharmacol. Ther."},{"key":"2026040911515875400_ref4","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer's disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol Med."},{"key":"2026040911515875400_ref5","doi-asserted-by":"crossref","DOI":"10.26508\/lsa.202402650","article-title":"Metabolic resistance of A\u03b23pE-42, a target epitope of the anti-Alzheimer therapeutic antibody, donanemab","volume":"7","author":"Iwata","year":"2024","journal-title":"Life Sci Alliance."},{"key":"2026040911515875400_ref6","doi-asserted-by":"crossref","DOI":"10.1523\/JNEUROSCI.2152-24.2025","article-title":"The role of neprilysin and insulin-degrading enzyme in the etiology of sporadic Alzheimer's disease","volume":"45","author":"Morito","year":"2025","journal-title":"J. Neurosci."},{"key":"2026040911515875400_ref7","article-title":"Somatostatin receptor subtypes 1 and 4 regulate neprilysin, the major amyloid \u03b2-degrading enzyme in brain","author":"Nilsson","year":"2025","journal-title":"J. Alzheimer's Dis"},{"key":"2026040911515875400_ref8","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/nm1206","article-title":"Somatostatin regulates brain amyloid \u03b2 peptide A\u03b242 through modulation of proteolytic degradation","volume":"11","author":"Saito","year":"2005","journal-title":"Nat. Med."},{"key":"2026040911515875400_ref9","doi-asserted-by":"crossref","first-page":"eadk1822","DOI":"10.1126\/scisignal.adk1822","article-title":"The dopaminergic system promotes neprilysin-mediated degradation of amyloid-\u03b2 in the brain","volume":"17","author":"Watamura","year":"2024","journal-title":"Sci. Signal."},{"key":"2026040911515875400_ref10","doi-asserted-by":"crossref","first-page":"29362","DOI":"10.1074\/jbc.M112.340372","article-title":"Cell surface expression of the major amyloid-\u03b2 peptide (A\u03b2)-degrading enzyme, neprilysin, depends on phosphorylation by mitogen-activated protein kinase\/extracellular signal-regulated kinase kinase (MEK) and dephosphorylation by protein phosphatase 1a","volume":"287","author":"Kakiya","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2026040911515875400_ref11","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1042\/bj3020451","article-title":"Role of glycosylation in transport and enzymic activity of neutral","volume":"302 ( Pt 2)","author":"Lafrance","year":"1994","journal-title":"Biochem. J."},{"key":"2026040911515875400_ref12","doi-asserted-by":"crossref","first-page":"7103","DOI":"10.1073\/pnas.86.18.7103","article-title":"Organization of the gene encoding common acute lymphoblastic leukemia antigen (neutral endopeptidase 24.11): multiple miniexons and separate 5\u2032 untranslated regions","volume":"86","author":"D\u2019Adamio","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2026040911515875400_ref13","doi-asserted-by":"crossref","first-page":"5723","DOI":"10.1074\/jbc.270.11.5723","article-title":"Tissue-specific expression of rat neutral endopeptidase (Neprilysin) mRNAs","volume":"270","author":"Li","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2026040911515875400_ref14","doi-asserted-by":"crossref","first-page":"27702","DOI":"10.1074\/jbc.M114.586719","article-title":"Pharmacological profile of brain-derived neurotrophic factor (BDNF) splice variant translation using a novel drug screening assay: a \u201cquantitative code\u201d","volume":"289","author":"Vaghi","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2026040911515875400_ref15","doi-asserted-by":"crossref","first-page":"16927","DOI":"10.1074\/jbc.R116.733899","article-title":"Upstream open reading frames differentially regulate gene-specific translation in the integrated stress response","volume":"291","author":"Young","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2026040911515875400_ref16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12860-020-00336-4","article-title":"Reduced translational output due to novel splicing variants in 5\u2032 untranslated region and identification of novel cis-regulatory elements in canine and human BRCA2","volume":"22","author":"Yoshikawa","year":"2021","journal-title":"BMC Mol Cell Biol."},{"key":"2026040911515875400_ref17","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.neuron.2015.05.004","article-title":"Alternative splicing in the mammalian nervous system: recent insights into mechanisms and functional roles","volume":"87","author":"Raj","year":"2015","journal-title":"Neuron."},{"key":"2026040911515875400_ref18","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/0378-1119(95)00464-H","article-title":"Comparison of the structure and expression of the human and rat neprilysin (endopeptidase 24.11)-encoding genes","volume":"164","author":"Li","year":"1995","journal-title":"Gene."},{"key":"2026040911515875400_ref19","doi-asserted-by":"crossref","first-page":"21895","DOI":"10.1074\/jbc.M008511200","article-title":"Neprilysin degrades both amyloid \u03b2 peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases","volume":"276","author":"Shirotani","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2026040911515875400_ref20","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1007\/s11626-024-00948-6","article-title":"Differentiation of SH-SY5Y neuroblastoma cells using retinoic acid and BDNF: a model for neuronal and synaptic differentiation in neurodegeneration","volume":"60","author":"Targett","year":"2024","journal-title":"In Vitro Cell Dev Biol Anim."},{"key":"2026040911515875400_ref21","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1038\/srep01472","article-title":"Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice","volume":"3","author":"Iwata","year":"2013","journal-title":"Sci. Rep."},{"key":"2026040911515875400_ref22","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1248\/bpb.b23-00830","article-title":"Identification and characterization of synaptic vesicle membrane protein VAT-1 homolog as a new catechin-binding protein","volume":"47","author":"Ikemizu","year":"2024","journal-title":"Biol. Pharm. Bull."},{"key":"2026040911515875400_ref23","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1093\/hmg\/ddu501","article-title":"CFTR mRNA expression is regulated by an upstream open reading frame and RNA secondary structure in its 5\u2032 untranslated region","volume":"24","author":"Lukowski","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2026040911515875400_ref24","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s11064-024-04293-8","article-title":"Dopamine D1-like receptor stimulation induces CREB, arc, and BDNF dynamic changes in differentiated SH-SY5Y cells","volume":"50","author":"Rivera-Maya","year":"2025","journal-title":"Neurochem. Res."},{"key":"2026040911515875400_ref25","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1038\/sj.onc.1210987","article-title":"Retinoic acid downregulates Rae1 leading to APC(Cdh1) activation and neuroblastoma SH-SY5Y differentiation","volume":"27","author":"Cuende","year":"2008","journal-title":"Oncogene."},{"key":"2026040911515875400_ref26","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.neuro.2008.11.001","article-title":"Effects of all-trans-retinoic acid on human SH-SY5Y neuroblastoma as in vitro model in neurotoxicity research","volume":"30","author":"Cheung","year":"2009","journal-title":"Neurotoxicology."},{"key":"2026040911515875400_ref27","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s12951-019-0482-2","article-title":"Silica nanoparticle-exposure during neuronal differentiation modulates dopaminergic and cholinergic phenotypes in SH-SY5Y cells","volume":"17","author":"Wiedmer","year":"2019","journal-title":"J. Nanobiotechnology."},{"key":"2026040911515875400_ref28","doi-asserted-by":"crossref","first-page":"7439","DOI":"10.3390\/ijms25137439","article-title":"Exploring the regulation of cytochrome P450 in SH-SY5Y cells: implications for the onset of neurodegenerative diseases","volume":"25","author":"Pifferi","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"2026040911515875400_ref29","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1111\/cns.14230","article-title":"The neurotrophic activities of brain-derived neurotrophic factor are potentiated by binding with apigenin, a common flavone in vegetables, in stimulating the receptor signaling","volume":"29","author":"Gao","year":"2023","journal-title":"CNS Neurosci Ther."},{"key":"2026040911515875400_ref30","doi-asserted-by":"crossref","first-page":"7355","DOI":"10.1007\/s12035-019-1605-3","article-title":"Cholinergic differentiation of human neuroblastoma SH-SY5Y cell line and its potential use as an in vitro model for Alzheimer\u2019s disease studies","volume":"56","author":"Medeiros","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"2026040911515875400_ref31","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13041-020-00680-8","article-title":"Distinct role of 5\u2032UTR sequences in dendritic trafficking of BDNF mRNA: additional mechanisms for the BDNF splice variants spatial code","volume":"14","author":"Colliva","year":"2021","journal-title":"Mol Brain."},{"key":"2026040911515875400_ref32","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13059-025-03507-8","article-title":"Decoding subcellular RNA localization one molecule at a time","volume":"26","author":"Biayna","year":"2025","journal-title":"Genome Biol."},{"key":"2026040911515875400_ref33","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.1038\/emboj.2011.278","article-title":"Mechanisms of dendritic mRNA transport and its role in synaptic tagging","volume":"30","author":"Doyle","year":"2011","journal-title":"EMBO J."},{"key":"2026040911515875400_ref34","doi-asserted-by":"crossref","first-page":"4150","DOI":"10.1074\/jbc.M110.167817","article-title":"MicroRNAs-10a and -10b contribute to retinoic acid-induced differentiation of neuroblastoma cells and target the alternative splicing regulatory factor SFRS1 (SF2\/ASF)","volume":"286","author":"Meseguer","year":"2011","journal-title":"J. Biol. Chem."}],"container-title":["The Journal of Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jb\/advance-article-pdf\/doi\/10.1093\/jb\/mvag002\/66379495\/mvag002.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jb\/article-pdf\/179\/4\/269\/66379495\/mvag002.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jb\/article-pdf\/179\/4\/269\/66379495\/mvag002.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T15:52:08Z","timestamp":1775749928000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jb\/article\/179\/4\/269\/8423087"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,13]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,1,13]]},"published-print":{"date-parts":[[2026,4,13]]}},"URL":"https:\/\/doi.org\/10.1093\/jb\/mvag002","relation":{},"ISSN":["0021-924X","1756-2651"],"issn-type":[{"value":"0021-924X","type":"print"},{"value":"1756-2651","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,4]]},"published":{"date-parts":[[2026,1,13]]}}}