{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T21:52:09Z","timestamp":1770414729506,"version":"3.49.0"},"reference-count":57,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2018,5,31]],"date-time":"2018-05-31T00:00:00Z","timestamp":1527724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["AG027956"],"award-info":[{"award-number":["AG027956"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["AG022550"],"award-info":[{"award-number":["AG022550"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY014227"],"award-info":[{"award-number":["EY014227"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY022774"],"award-info":[{"award-number":["EY022774"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY027005"],"award-info":[{"award-number":["EY027005"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000097","name":"National Center for Research Resources","doi-asserted-by":"publisher","award":["RR027093"],"award-info":[{"award-number":["RR027093"]}],"id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A major cause underlying familial Alzheimer\u2019s disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the \u03b3-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta (A\u03b2). Consequently, presenilins have been the target of numerous and varied research efforts to develop therapeutic strategies for AD. The presenilin 1 gene harbors the largest number of AD-causing mutations resulting in the late onset familial form of AD. As a result, the majority of efforts for drug development focused on PS1 and A\u03b2. Soon after the discovery of the major involvement of PS1 and PS2 in \u03b3-secretase activity, it became clear that neuronal signaling, particularly calcium ion (Ca2+) signaling, is regulated by presenilins and impacted by mutations in presenilin genes. Intracellular Ca2+ signaling not only controls the activity of neurons, but also gene expression patterns, structural functionality of the cytoskeleton, synaptic connectivity and viability. Here, we will briefly review the role of presenilins in \u03b3-secretase activity, then focus on the regulation of Ca2+ signaling, oxidative stress, and cellular viability by presenilins within the context of AD and discuss the relevance of presenilins in AD drug development efforts.<\/jats:p>","DOI":"10.3390\/ijms19061621","type":"journal-article","created":{"date-parts":[[2018,5,31]],"date-time":"2018-05-31T03:07:42Z","timestamp":1527736062000},"page":"1621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Presenilins as Drug Targets for Alzheimer\u2019s Disease\u2014Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development"],"prefix":"10.3390","volume":"19","author":[{"given":"R. Scott","family":"Duncan","sequence":"first","affiliation":[{"name":"Vision Research Center, Department of Ophthalmology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bob","family":"Song","sequence":"additional","affiliation":[{"name":"Vision Research Center, Department of Ophthalmology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Koulen","sequence":"additional","affiliation":[{"name":"Vision Research Center, Department of Ophthalmology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"},{"name":"Department of Biomedical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/ng1095-219","article-title":"The structure of presenilin 1(S182) gene and identification of six novel mutation in early onset AD families","volume":"11","author":"Clark","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7977","DOI":"10.1074\/jbc.272.12.7977","article-title":"Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins","volume":"272","author":"Xia","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"22122","DOI":"10.1074\/jbc.M111.236257","article-title":"Amyloid-\u03b2 annular protofibrils evade fibrillar fate in Alzheimer disease brain","volume":"286","author":"Glabe","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1046\/j.1471-4159.1998.70010001.x","article-title":"Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer\u2019s disease","volume":"70","author":"Mattson","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1007\/s00702-015-1450-0","article-title":"Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer\u2019s disease","volume":"122","author":"Roeber","year":"2015","journal-title":"J. Neural Transm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.mcn.2015.06.002","article-title":"Decrease in catalytic capacity of \u03b3-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer\u2019s disease","volume":"67","year":"2015","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1093\/hmg\/ddv110","article-title":"Alzheimer\u2019s disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of \u03b3-secretase activity","volume":"24","author":"Newman","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.nbd.2016.02.008","article-title":"The dynamic mechanism of presenilin-1 function: Sensitive gate dynamics and loop unplugging control protein access","volume":"89","author":"Somavarapu","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16298","DOI":"10.1074\/jbc.M109.000067","article-title":"APH1 polar transmembrane residues regulate the assembly and activity of presenilin complexes","volume":"284","author":"Yang","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Svedru\u017ei\u0107, Z.M., Popovi\u0107, K., Smoljan, I., and Sendula-Jengi\u0107, V. (2012). Modulation of \u03b3-secretase activity by multiple enzyme-substrate interactions: Implications in pathogenesis of Alzheimer\u2019s disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032293"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7169","DOI":"10.1074\/jbc.M114.601286","article-title":"Presenilin transmembrane domain 8 conserved AXXXAXXXG motifs are required for the activity of the \u03b3-secretase complex","volume":"290","author":"Marinangeli","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9710","DOI":"10.1074\/jbc.M112.398602","article-title":"\u03b3-Secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on presenilin","volume":"288","author":"Pozdnyakov","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"40629","DOI":"10.1074\/jbc.M112.418442","article-title":"Retention in endoplasmic reticulum 1 (RER1) modulates amyloid-\u03b2 (A\u03b2) production by altering trafficking of \u03b3-secretase and amyloid precursor protein (APP)","volume":"287","author":"Park","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15352","DOI":"10.1074\/jbc.M112.441840","article-title":"Interactome analyses of mature \u03b3-secretase complexes reveal distinct molecular environments of presenilin (PS) paralogs and preferential binding of signal peptide peptidase to PS2","volume":"288","author":"Jeon","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1242\/dmm.004457","article-title":"Dictyostelium possesses highly diverged presenilin\/gamma-secretase that regulates growth and cell-fate specification and can accurately process human APP: A system for functional studies of the presenilin\/gamma-secretase complex","volume":"3","author":"McMains","year":"2010","journal-title":"Dis. Models Mech."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"745","DOI":"10.2174\/1567205012666150710110756","article-title":"Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer\u2019s disease","volume":"12","author":"Coupland","year":"2015","journal-title":"Curr. Alzheimer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.1993.tb18285.x","article-title":"Altered calcium signaling and neuronal injury: Stroke and Alzheimer\u2019s disease as examples","volume":"679","author":"Mattson","year":"1993","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/ana.410380304","article-title":"Aging, energy, and oxidative stress in neurodegenerative diseases","volume":"38","author":"Beal","year":"1995","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/nature08177","article-title":"Presenilins are essential for regulating neurotransmitter release","volume":"460","author":"Zhang","year":"2009","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.1016\/j.neurobiolaging.2015.09.007","article-title":"Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant","volume":"36","author":"Kim","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.brainres.2015.12.020","article-title":"Single administration of a novel \u03b3-secretase modulator ameliorates cognitive dysfunction in aged C57BL\/6J mice","volume":"1633","author":"Hayama","year":"2016","journal-title":"Brain Res."},{"key":"ref_22","first-page":"e449","article-title":"Regulation of ryanodine receptor-mediated calcium signaling by presenilins","volume":"2","author":"Payne","year":"2015","journal-title":"Recept. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Grillo, M.A., Grillo, S.L., Gerdes, B.C., Kraus, J.G., and Koulen, P. (2018). Control of Neuronal Ryanodine Receptor-Mediated Calcium Signaling by Calsenilin. Mol. Neurobiol., 1\u201310.","DOI":"10.1007\/s12035-018-1080-2"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s12035-014-8877-4","article-title":"Loss of Spatial Memory, Learning, and Motor Function During Normal Aging Is Accompanied by Changes in Brain Presenilin 1 and 2 Expression Levels","volume":"52","author":"Kaja","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.expneurol.2013.09.001","article-title":"Presenilins regulate the cellular activity of ryanodine receptors differentially through isotype-specific N-terminal cysteines","volume":"250","author":"Payne","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15091","DOI":"10.1073\/pnas.1304171110","article-title":"Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons","volume":"110","author":"Wu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1016\/j.neurobiolaging.2012.12.013","article-title":"\u03b2 amyloid peptide plaques fail to alter evoked neuronal calcium signals in APP\/PS1 Alzheimer\u2019s disease mice","volume":"34","author":"Briggs","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Michno, K., Knight, D., Campusano, J.M., van de Hoef, D., and Boulianne, G.L. (2009). Intracellular calcium deficits in Drosophila cholinergic neurons expressing wild type or FAD-mutant presenilin. PLoS ONE, 4.","DOI":"10.1371\/annotation\/f8cecc73-06ec-4bba-b07a-a3bc2a08f4c7"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1016\/j.celrep.2015.07.050","article-title":"Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification","volume":"12","author":"Lee","year":"2015","journal-title":"Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.neuroscience.2015.07.011","article-title":"Oxidative stress caused by ozone exposure induces \u03b2-amyloid 1\u201342 overproduction and mitochondrial accumulation by activating the amyloidogenic pathway","volume":"304","year":"2015","journal-title":"Neuroscience"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1002\/glia.22886","article-title":"Dual pathways mediate \u03b2-amyloid stimulated glutathione release from astrocytes","volume":"63","author":"Ye","year":"2015","journal-title":"Glia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.neurobiolaging.2016.02.028","article-title":"Presenilin 1 promotes trypsin-induced neuroprotection via the PAR2\/ERK signaling pathway. Effects of presenilin 1 FAD mutations","volume":"42","author":"Nikolakopoulou","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1534\/genetics.115.182808","article-title":"A \u03b3-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans","volume":"201","author":"Sarasija","year":"2015","journal-title":"Genetics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.bbamcr.2015.01.017","article-title":"Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-\u03baB activation: Use of insulin to attenuate metformin\u2019s effect","volume":"1853","author":"Picone","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10582","DOI":"10.1523\/JNEUROSCI.1736-09.2009","article-title":"Beta-amyloid monomers are neuroprotective","volume":"29","author":"Giuffrida","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1007\/s11011-015-9667-z","article-title":"Alterations in mitochondrial number and function in Alzheimer\u2019s disease fibroblasts","volume":"30","author":"Gray","year":"2015","journal-title":"Metab. Brain Dis."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Southon, A., Greenough, M.A., Ganio, G., Bush, A.I., Burke, R., and Camakaris, J. (2013). Presenilin promotes dietary copper uptake. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062811"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"581","DOI":"10.3233\/JAD-150678","article-title":"The Zebrafish Equivalent of Alzheimer\u2019s Disease-Associated PRESENILIN Isoform PS2V Regulates Inflammatory and Other Responses to Hypoxic Stress","volume":"52","author":"Ebrahimie","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1007\/s13238-011-1073-7","article-title":"Antioxidant proteins TSA and PAG interact synergistically with Presenilin to modulate Notch signaling in Drosophila","volume":"2","author":"Wangler","year":"2011","journal-title":"Protein Cell"},{"key":"ref_40","first-page":"130","article-title":"\u03b2-amyloid (A\u03b2) deposition in cognitively normal brain, dementia with Lewy bodies, and Alzheimer\u2019s disease: A study using principal components analysis","volume":"50","author":"Armstrong","year":"2012","journal-title":"Folia Neuropathol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Means, J.C., Gerdes, B.C., and Koulen, P. (2017). Distinct Mechanisms Underlying Resveratrol-Mediated Protection from Types of Cellular Stress in C6 Glioma Cells. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071521"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1093\/cvr\/cvt029","article-title":"Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy","volume":"98","author":"Pedrozo","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.bbi.2015.11.013","article-title":"Acceleration of amyloidogenesis and memory impairment by estrogen deficiency through NF-\u03baB dependent beta-secretase activation in presenilin 2 mutant mice","volume":"53","author":"Hwang","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_44","first-page":"1576","article-title":"An ancestral non-proteolytic role for presenilin proteins in multicellular development of the social amoeba Dictyostelium discoideum","volume":"127","author":"Ludtmann","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.febslet.2015.03.008","article-title":"A ubiquitin-binding CUE domain in presenilin-1 enables interaction with K63-linked polyubiquitin chains","volume":"589","author":"Duggan","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.brainres.2012.10.036","article-title":"Presenilin-null cells have altered two-pore calcium channel expression and lysosomal calcium: Implications for lysosomal function","volume":"1489","author":"Dickinson","year":"2012","journal-title":"Brain Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1523\/JNEUROSCI.5156-10.2010","article-title":"Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a \u03b3-secretase-independent manner","volume":"31","author":"Neely","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8633","DOI":"10.1523\/JNEUROSCI.0556-12.2012","article-title":"A role for presenilins in autophagy revisited: Normal acidification of lysosomes in cells lacking PSEN1 and PSEN2","volume":"32","author":"Zhang","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"35222","DOI":"10.1074\/jbc.M113.513705","article-title":"Presenilins regulate neurotrypsin gene expression and neurotrypsin-dependent agrin cleavage via cyclic AMP response element-binding protein (CREB) modulation","volume":"288","author":"Kim","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"313","DOI":"10.2174\/156720511795563746","article-title":"Changes in the expression of the Alzheimer\u2019s disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction","volume":"8","author":"Li","year":"2011","journal-title":"Curr. Alzheimer Res."},{"key":"ref_51","first-page":"217","article-title":"Mutation analyses and association studies to assess the role of the presenilin-associated rhomboid-like gene in Parkinson\u2019s disease","volume":"39","author":"Maurer","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10650","DOI":"10.18632\/oncotarget.7298","article-title":"The expression of presenilin 1 enhances carcinogenesis and metastasis in gastric cancer","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1097\/JTO.0000000000000493","article-title":"Hippo pathway gene mutations in malignant mesothelioma: Revealed by RNA and targeted exon sequencing","volume":"10","author":"Miyanaga","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1016\/j.jaad.2015.07.045","article-title":"Pathophysiology of hidradenitis suppurativa: An update","volume":"73","author":"Prens","year":"2015","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1159\/000382122","article-title":"A Frameshift Mutation in PEN-2 Causes Familial Comedones Syndrome","volume":"231","author":"Panmontha","year":"2015","journal-title":"Dermatology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.3233\/JAD-142259","article-title":"Overexpression of mutant amyloid-\u03b2 protein precursor and presenilin 1 modulates enteric nervous system","volume":"44","author":"Puig","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.1101\/gad.13.21.2801","article-title":"Mice lacking both presenilin genes exhibit early embryonic patterning defects","volume":"13","author":"Donoviel","year":"1999","journal-title":"Genes Dev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/6\/1621\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:06:36Z","timestamp":1760195196000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/6\/1621"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,31]]},"references-count":57,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["ijms19061621"],"URL":"https:\/\/doi.org\/10.3390\/ijms19061621","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,31]]}}}