{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:26:23Z","timestamp":1788351983519,"version":"build-2803163510"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T00:00:00Z","timestamp":1568160000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T00:00:00Z","timestamp":1568160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100006955","name":"U.S. Department of Health &amp; Human Services | NIH | Office of Extramural Research, National Institutes of Health","doi-asserted-by":"publisher","award":["NS 092145"],"award-info":[{"award-number":["NS 092145"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Endothelial-to-mesenchyme-like transition (Endo-MT) of trabecular meshwork (TM) cells is known to be associated with primary open angle glaucoma (POAG). Here, we investigated whether the prion protein (PrP<jats:sup>C<\/jats:sup>), a neuronal protein known to modulate epithelial-to-mesenchymal transition in a variety of cell types, is expressed in the TM, and plays a similar role at this site. Using a combination of primary human TM cells and human, bovine, and PrP-knock-out (PrP<jats:sup>\u2212\/\u2212<\/jats:sup>) mouse models, we demonstrate that PrP<jats:sup>C<\/jats:sup> is expressed in the TM of all three species, including endothelial cells lining the Schlemm\u2019s canal. Silencing of PrP<jats:sup>C<\/jats:sup> in primary human TM cells induces aggregation of \u03b21-integrin and upregulation of \u03b1-smooth muscle actin, fibronectin, collagen 1A, vimentin, and laminin, suggestive of transition to a mesenchyme-like phenotype. Remarkably, intraocular pressure is significantly elevated in PrP<jats:sup>\u2212\/\u2212<\/jats:sup> mice relative to wild-type controls, suggesting reduced pliability of the extracellular matrix and increased resistance to aqueous outflow in the absence of PrP<jats:sup>C<\/jats:sup>. Since PrP<jats:sup>C<\/jats:sup> is cleaved by members of the disintegrin and matrix-metalloprotease family that are increased in the aqueous humor of POAG arising from a variety of conditions, it is likely that concomitant cleavage of PrP<jats:sup>C<\/jats:sup> exaggerates and confounds the pathology by inducing Endo-MT-like changes in the TM.<\/jats:p>","DOI":"10.1038\/s41598-019-49482-6","type":"journal-article","created":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T10:03:02Z","timestamp":1568196182000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Prion protein modulates endothelial to mesenchyme-like transition in trabecular meshwork cells: Implications for primary open angle glaucoma"],"prefix":"10.1038","volume":"9","author":[{"given":"Ajay","family":"Ashok","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min H.","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron S.","family":"Wise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Pattabiraman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lonigro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjana","family":"Ravikumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas J.","family":"Rhee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neena","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,11]]},"reference":[{"key":"49482_CR1","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1126\/science.1222951","volume":"336","author":"SB Prusiner","year":"2012","unstructured":"Prusiner, S. B. A unifying role for prions in neurodegenerative diseases. Science 336, 1511\u20131513 (2012).","journal-title":"Science"},{"issue":"2","key":"49482_CR2","doi-asserted-by":"publisher","first-page":"169","DOI":"10.4161\/pri.27836","volume":"8","author":"Ilia V Baskakov","year":"2014","unstructured":"Baskakov, I. V. The many shades of prion strain adaptation. Prion 8 (2014).","journal-title":"Prion"},{"key":"49482_CR3","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1042\/bse0560181","volume":"56","author":"J Ma","year":"2014","unstructured":"Ma, J. & Wang, F. Prion disease and the \u2018protein-only hypothesis\u2019. Essays in biochemistry 56, 181\u2013191, https:\/\/doi.org\/10.1042\/bse0560181 (2014).","journal-title":"Essays in biochemistry"},{"key":"49482_CR4","doi-asserted-by":"crossref","unstructured":"Singh, N. The Role of Iron in Prion Disease and Other Neurodegenerative Diseases. Vol. 10 (2014).","DOI":"10.1371\/journal.ppat.1004335"},{"key":"49482_CR5","doi-asserted-by":"publisher","first-page":"e1005073","DOI":"10.1371\/journal.ppat.1005073","volume":"11","author":"A Alleaume-Butaux","year":"2015","unstructured":"Alleaume-Butaux, A. et al. Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation. PLoS Pathog 11, e1005073, https:\/\/doi.org\/10.1371\/journal.ppat.1005073 (2015).","journal-title":"PLoS Pathog"},{"key":"49482_CR6","doi-asserted-by":"publisher","unstructured":"Zhong, Z. et al. Prion-like protein aggregates exploit the RHO GTPase to cofilin-1 signaling pathway to enter cells. EMBO J 37, https:\/\/doi.org\/10.15252\/embj.201797822 (2018).","DOI":"10.15252\/embj.201797822"},{"key":"49482_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.37","volume":"8","author":"HJ Kim","year":"2017","unstructured":"Kim, H. J. et al. Regulation of RhoA activity by the cellular prion protein. Cell Death Dis 8, e2668, https:\/\/doi.org\/10.1038\/cddis.2017.37 (2017).","journal-title":"Cell Death Dis"},{"key":"49482_CR8","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1096\/fj.11-185579","volume":"26","author":"D Loubet","year":"2012","unstructured":"Loubet, D. et al. Neuritogenesis: the prion protein controls beta1 integrin signaling activity. FASEB J 26, 678\u2013690, https:\/\/doi.org\/10.1096\/fj.11-185579 (2012).","journal-title":"FASEB J"},{"key":"49482_CR9","first-page":"63","volume":"12","author":"VR Martins","year":"2010","unstructured":"Martins, V. R. et al. Prion protein: orchestrating neurotrophic activities. Current issues in molecular biology 12, 63 (2010).","journal-title":"Current issues in molecular biology"},{"key":"49482_CR10","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.1111\/j.1471-4159.2007.04904.x","volume":"103","author":"FR Lima","year":"2007","unstructured":"Lima, F. R. et al. Cellular prion protein expression in astrocytes modulates neuronal survival and differentiation. J Neurochem 103, 2164\u20132176, https:\/\/doi.org\/10.1111\/j.1471-4159.2007.04904.x (2007).","journal-title":"J Neurochem"},{"key":"49482_CR11","doi-asserted-by":"publisher","first-page":"53","DOI":"10.3389\/fcell.2014.00053","volume":"2","author":"M Mehrabian","year":"2014","unstructured":"Mehrabian, M., Ehsani, S. & Schmitt-Ulms, G. An emerging role of the cellular prion protein as a modulator of a morphogenetic program underlying epithelial-to-mesenchymal transition. Front Cell Dev Biol 2, 53, https:\/\/doi.org\/10.3389\/fcell.2014.00053 (2014).","journal-title":"Front Cell Dev Biol"},{"key":"49482_CR12","doi-asserted-by":"crossref","unstructured":"Abu-Hassan, D. W., Acott, T. S. & Kelley, M. J. The trabecular meshwork: a basic review of form and function. Journal of ocular biology 2 (2014).","DOI":"10.13188\/2334-2838.1000017"},{"key":"49482_CR13","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.exer.2016.08.023","volume":"158","author":"PV Rao","year":"2017","unstructured":"Rao, P. V., Pattabiraman, P. P. & Kopczynski, C. Role of the Rho GTPase\/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research. Exp Eye Res 158, 23\u201332, https:\/\/doi.org\/10.1016\/j.exer.2016.08.023 (2017).","journal-title":"Exp Eye Res"},{"key":"49482_CR14","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1002\/jcp.24524","volume":"229","author":"PP Pattabiraman","year":"2014","unstructured":"Pattabiraman, P. P., Maddala, R. & Rao, P. V. Regulation of plasticity and fibrogenic activity of trabecular meshwork cells by Rho GTPase signaling. J Cell Physiol 229, 927\u2013942, https:\/\/doi.org\/10.1002\/jcp.24524 (2014).","journal-title":"J Cell Physiol"},{"key":"49482_CR15","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.ejpb.2015.04.029","volume":"95","author":"BM Braunger","year":"2015","unstructured":"Braunger, B. M., Fuchshofer, R. & Tamm, E. R. The aqueous humor outflow pathways in glaucoma: A unifying concept of disease mechanisms and causative treatment. Eur J Pharm Biopharm 95, 173\u2013181, https:\/\/doi.org\/10.1016\/j.ejpb.2015.04.029 (2015).","journal-title":"Eur J Pharm Biopharm"},{"key":"49482_CR16","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.1001\/jama.2014.3192","volume":"311","author":"RN Weinreb","year":"2014","unstructured":"Weinreb, R. N., Aung, T. & Medeiros, F. A. The pathophysiology and treatment of glaucoma: a review. JAMA 311, 1901\u20131911, https:\/\/doi.org\/10.1001\/jama.2014.3192 (2014).","journal-title":"JAMA"},{"key":"49482_CR17","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1016\/j.ophtha.2018.04.040","volume":"125","author":"AP Tanna","year":"2018","unstructured":"Tanna, A. P. & Johnson, M. Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension. Ophthalmology 125, 1741\u20131756, https:\/\/doi.org\/10.1016\/j.ophtha.2018.04.040 (2018).","journal-title":"Ophthalmology"},{"key":"49482_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/srep38319","volume":"6","author":"KY Torrejon","year":"2016","unstructured":"Torrejon, K. Y. et al. TGFbeta2-induced outflow alterations in a bioengineered trabecular meshwork are offset by a rho-associated kinase inhibitor. Sci Rep 6, 38319, https:\/\/doi.org\/10.1038\/srep38319 (2016).","journal-title":"Sci Rep"},{"key":"49482_CR19","doi-asserted-by":"publisher","first-page":"2368","DOI":"10.1038\/onc.2009.514","volume":"29","author":"N Garamszegi","year":"2010","unstructured":"Garamszegi, N. et al. Extracellular matrix-induced transforming growth factor-beta receptor signaling dynamics. Oncogene 29, 2368\u20132380, https:\/\/doi.org\/10.1038\/onc.2009.514 (2010).","journal-title":"Oncogene"},{"key":"49482_CR20","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1089\/jop.2013.0176","volume":"30","author":"D Gagen","year":"2014","unstructured":"Gagen, D., Faralli, J. A., Filla, M. S. & Peters, D. M. The role of integrins in the trabecular meshwork. J Ocul Pharmacol Ther 30, 110\u2013120, https:\/\/doi.org\/10.1089\/jop.2013.0176 (2014).","journal-title":"J Ocul Pharmacol Ther"},{"key":"49482_CR21","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1111\/j.1582-4934.2011.01419.x","volume":"16","author":"FA Mamuya","year":"2012","unstructured":"Mamuya, F. A. & Duncan, M. K. aV integrins and TGF-beta-induced EMT: a circle of regulation. J Cell Mol Med 16, 445\u2013455, https:\/\/doi.org\/10.1111\/j.1582-4934.2011.01419.x (2012).","journal-title":"J Cell Mol Med"},{"key":"49482_CR22","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1167\/iovs.16-19672","volume":"58","author":"M Montecchi-Palmer","year":"2017","unstructured":"Montecchi-Palmer, M. et al. TGFbeta2 Induces the Formation of Cross-Linked Actin Networks (CLANs) in Human Trabecular Meshwork Cells Through the Smad and Non-Smad Dependent Pathways. Invest Ophthalmol Vis Sci 58, 1288\u20131295, https:\/\/doi.org\/10.1167\/iovs.16-19672 (2017).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"49482_CR23","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1167\/iovs.17-22807","volume":"59","author":"M Honjo","year":"2018","unstructured":"Honjo, M. et al. Role of the Autotaxin-LPA Pathway in Dexamethasone-Induced Fibrotic Responses and Extracellular Matrix Production in Human Trabecular Meshwork Cells. Invest Ophthalmol Vis Sci 59, 21\u201330, https:\/\/doi.org\/10.1167\/iovs.17-22807 (2018).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"49482_CR24","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.exer.2013.11.014","volume":"118","author":"E Takahashi","year":"2014","unstructured":"Takahashi, E., Inoue, T., Fujimoto, T., Kojima, S. & Tanihara, H. Epithelial mesenchymal transition-like phenomenon in trabecular meshwork cells. Exp Eye Res 118, 72\u201379, https:\/\/doi.org\/10.1016\/j.exer.2013.11.014 (2014).","journal-title":"Exp Eye Res"},{"key":"49482_CR25","doi-asserted-by":"publisher","first-page":"a005017","DOI":"10.1101\/cshperspect.a005017","volume":"3","author":"JS Munger","year":"2011","unstructured":"Munger, J. S. & Sheppard, D. Cross talk among TGF-beta signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb Perspect Biol 3, a005017, https:\/\/doi.org\/10.1101\/cshperspect.a005017 (2011).","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"49482_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-26685-x","volume":"8","author":"F Ghodrati","year":"2018","unstructured":"Ghodrati, F. et al. The prion protein is embedded in a molecular environment that modulates transforming growth factor beta and integrin signaling. Sci Rep 8, 8654, https:\/\/doi.org\/10.1038\/s41598-018-26685-x (2018).","journal-title":"Sci Rep"},{"key":"49482_CR27","doi-asserted-by":"publisher","first-page":"2635","DOI":"10.1167\/iovs.17-23434","volume":"59","author":"S Sharma","year":"2018","unstructured":"Sharma, S. et al. Proteomic Alterations in Aqueous Humor From Patients With Primary Open Angle Glaucoma. Invest Ophthalmol Vis Sci 59, 2635\u20132643, https:\/\/doi.org\/10.1167\/iovs.17-23434 (2018).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"49482_CR28","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.bbrc.2016.01.038","volume":"470","author":"M Gil","year":"2016","unstructured":"Gil, M. et al. Cellular prion protein regulates invasion and migration of breast cancer cells through MMP-9 activity. Biochem Biophys Res Commun 470, 213\u2013219, https:\/\/doi.org\/10.1016\/j.bbrc.2016.01.038 (2016).","journal-title":"Biochem Biophys Res Commun"},{"key":"49482_CR29","doi-asserted-by":"publisher","first-page":"5712341","DOI":"10.1155\/2017\/5712341","volume":"2017","author":"AC Gauthier","year":"2017","unstructured":"Gauthier, A. C. & Liu, J. Epigenetics and Signaling Pathways in Glaucoma. Biomed Res Int 2017, 5712341, https:\/\/doi.org\/10.1155\/2017\/5712341 (2017).","journal-title":"Biomed Res Int"},{"key":"49482_CR30","doi-asserted-by":"crossref","unstructured":"Ashok, A. et al. Prion protein modulates iron transport in the anterior segment: Implications for ocular iron homeostasis and prion transmission. Experimental eye research (2018).","DOI":"10.1016\/j.exer.2018.05.031"},{"key":"49482_CR31","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1046\/j.1471-4159.2003.01255.x","volume":"84","author":"Y Gu","year":"2003","unstructured":"Gu, Y. et al. Mutant prion protein\u2010mediated aggregation of normal prion protein in the endoplasmic reticulum: implications for prion propagation and neurotoxicity. Journal of neurochemistry 84, 10\u201322 (2003).","journal-title":"Journal of neurochemistry"},{"key":"49482_CR32","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.exer.2014.08.015","volume":"128","author":"C-YC Yang","year":"2014","unstructured":"Yang, C.-Y. C., Huynh, T., Johnson, M. & Gong, H. Endothelial glycocalyx layer in the aqueous outflow pathway of bovine and human eyes. Experimental eye research 128, 27\u201333 (2014).","journal-title":"Experimental eye research"},{"key":"49482_CR33","first-page":"15","volume":"1","author":"HC Altmeppen","year":"2012","unstructured":"Altmeppen, H. C. et al. Proteolytic processing of the prion protein in health and disease. Am J Neurodegener Dis 1, 15\u201331 (2012).","journal-title":"Am J Neurodegener Dis"},{"key":"49482_CR34","doi-asserted-by":"publisher","first-page":"7097","DOI":"10.1167\/iovs.12-9989","volume":"53","author":"T Fujimoto","year":"2012","unstructured":"Fujimoto, T. et al. Involvement of RhoA\/Rho-associated kinase signal transduction pathway in dexamethasone-induced alterations in aqueous outflow. Invest Ophthalmol Vis Sci 53, 7097\u20137108, https:\/\/doi.org\/10.1167\/iovs.12-9989 (2012).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"49482_CR35","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.exer.2018.03.001","volume":"171","author":"KE Keller","year":"2018","unstructured":"Keller, K. E. et al. Consensus recommendations for trabecular meshwork cell isolation, characterization and culture. Exp Eye Res 171, 164\u2013173, https:\/\/doi.org\/10.1016\/j.exer.2018.03.001 (2018).","journal-title":"Exp Eye Res"},{"key":"49482_CR36","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1080\/13506129.2017.1289913","volume":"24","author":"M Nuvolone","year":"2017","unstructured":"Nuvolone, M., Sorce, S., Paolucci, M. & Aguzzi, A. Extended characterization of the novel co-isogenic C57BL\/6J Prnp(\u2212\/\u2212) mouse line. Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 24, 36\u201337, https:\/\/doi.org\/10.1080\/13506129.2017.1289913 (2017).","journal-title":"Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis"},{"key":"49482_CR37","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1084\/jem.20151610","volume":"213","author":"M Nuvolone","year":"2016","unstructured":"Nuvolone, M. et al. Strictly co-isogenic C57BL\/6J-Prnp\u2212\/\u2212 mice: A rigorous resource for prion science. The Journal of experimental medicine 213, 313\u2013327, https:\/\/doi.org\/10.1084\/jem.20151610 (2016).","journal-title":"The Journal of experimental medicine"},{"key":"49482_CR38","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/j.exer.2008.01.013","volume":"86","author":"TS Acott","year":"2008","unstructured":"Acott, T. S. & Kelley, M. J. Extracellular matrix in the trabecular meshwork. Experimental eye research 86, 543\u2013561, https:\/\/doi.org\/10.1016\/j.exer.2008.01.013 (2008).","journal-title":"Experimental eye research"},{"key":"49482_CR39","doi-asserted-by":"publisher","first-page":"19173","DOI":"10.1074\/jbc.270.32.19173","volume":"270","author":"SG Chen","year":"1995","unstructured":"Chen, S. G. et al. Truncated forms of the human prion protein in normal brain and in prion diseases. Journal of Biological Chemistry 270, 19173\u201319180 (1995).","journal-title":"Journal of Biological Chemistry"},{"key":"49482_CR40","doi-asserted-by":"publisher","first-page":"35914","DOI":"10.1074\/jbc.M507327200","volume":"280","author":"NT Watt","year":"2005","unstructured":"Watt, N. T. et al. Reactive oxygen species-mediated beta-cleavage of the prion protein in the cellular response to oxidative stress. J Biol Chem 280, 35914\u201335921, https:\/\/doi.org\/10.1074\/jbc.M507327200 (2005).","journal-title":"J Biol Chem"},{"key":"49482_CR41","doi-asserted-by":"publisher","first-page":"4338","DOI":"10.1111\/febs.12196","volume":"280","author":"HC Altmeppen","year":"2013","unstructured":"Altmeppen, H. C. et al. Roles of endoproteolytic alpha-cleavage and shedding of the prion protein in neurodegeneration. FEBS J 280, 4338\u20134347, https:\/\/doi.org\/10.1111\/febs.12196 (2013).","journal-title":"FEBS J"},{"key":"49482_CR42","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1007\/s00018-015-2022-z","volume":"73","author":"V Lewis","year":"2016","unstructured":"Lewis, V. et al. Prion protein \u201cgamma-cleavage\u201d: characterizing a novel endoproteolytic processing event. Cell Mol Life Sci 73, 667\u2013683, https:\/\/doi.org\/10.1007\/s00018-015-2022-z (2016).","journal-title":"Cell Mol Life Sci"},{"key":"49482_CR43","doi-asserted-by":"crossref","unstructured":"Ashok, A. & Singh, N. Prion protein modulates glucose homeostasis by altering intracellular iron. Scientific reports 8 (2018).","DOI":"10.1038\/s41598-018-24786-1"},{"key":"49482_CR44","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08821-1","volume":"7","author":"A Asthana","year":"2017","unstructured":"Asthana, A. et al. Prion protein facilitates retinal iron uptake and is cleaved at the \u03b2-site: Implications for retinal iron homeostasis in prion disorders. Scientific reports 7, 9600 (2017).","journal-title":"Scientific reports"},{"key":"49482_CR45","doi-asserted-by":"publisher","first-page":"2128","DOI":"10.1016\/j.bbamcr.2017.06.022","volume":"1864","author":"L Linsenmeier","year":"2017","unstructured":"Linsenmeier, L. et al. Diverse functions of the prion protein - Does proteolytic processing hold the key? Biochim Biophys Acta Mol Cell Res 1864, 2128\u20132137, https:\/\/doi.org\/10.1016\/j.bbamcr.2017.06.022 (2017).","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"key":"49482_CR46","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1016\/j.exer.2010.03.003","volume":"90","author":"S Garcia-Castineiras","year":"2010","unstructured":"Garcia-Castineiras, S. Iron, the retina and the lens: a focused review. Experimental eye research 90, 664\u2013678, https:\/\/doi.org\/10.1016\/j.exer.2010.03.003 (2010).","journal-title":"Experimental eye research"},{"key":"49482_CR47","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1111\/febs.12654","volume":"281","author":"CE Mays","year":"2014","unstructured":"Mays, C. E. et al. Endoproteolytic processing of the mammalian prion glycoprotein family. The FEBS journal 281, 862\u2013876 (2014).","journal-title":"The FEBS journal"},{"key":"49482_CR48","doi-asserted-by":"publisher","first-page":"183","DOI":"10.4161\/pri.28796","volume":"8","author":"AJ McDonald","year":"2014","unstructured":"McDonald, A. J. & Millhauser, G. L. PrP overdrive: Does inhibition of \u03b1-cleavage contribute to PrPC toxicity and prion disease? Prion 8, 183\u2013191 (2014).","journal-title":"Prion"},{"key":"49482_CR49","doi-asserted-by":"publisher","first-page":"238","DOI":"10.4103\/1673-5374.177726","volume":"11","author":"CL Haigh","year":"2016","unstructured":"Haigh, C. L. & Collins, S. J. Endoproteolytic cleavage as a molecular switch regulating and diversifying prion protein function. Neural regeneration research 11, 238 (2016).","journal-title":"Neural regeneration research"},{"key":"49482_CR50","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1074\/jbc.M113.502351","volume":"289","author":"AJ McDonald","year":"2014","unstructured":"McDonald, A. J., Dibble, J. P., Evans, E. G. & Millhauser, G. L. A new paradigm for enzymatic control of \u03b1-cleavage and \u03b2-cleavage of the prion protein. Journal of Biological Chemistry 289, 803\u2013813 (2014).","journal-title":"Journal of Biological Chemistry"},{"key":"49482_CR51","doi-asserted-by":"publisher","first-page":"7085","DOI":"10.1074\/jbc.RA118.005364","volume":"294","author":"HH Jarosz-Griffiths","year":"2019","unstructured":"Jarosz-Griffiths, H. H. et al. Proteolytic shedding of the prion protein via activation of metallopeptidase ADAM10 reduces cellular binding and toxicity of amyloid-\u03b2 oligomers. Journal of Biological Chemistry 294, 7085\u20137097 (2019).","journal-title":"Journal of Biological Chemistry"},{"key":"49482_CR52","doi-asserted-by":"publisher","first-page":"e04260","DOI":"10.7554\/eLife.04260","volume":"4","author":"HC Altmeppen","year":"2015","unstructured":"Altmeppen, H. C. et al. The sheddase ADAM10 is a potent modulator of prion disease. Elife 4, e04260 (2015).","journal-title":"Elife"},{"key":"49482_CR53","doi-asserted-by":"publisher","first-page":"22590","DOI":"10.1074\/jbc.M109.032599","volume":"284","author":"DR Taylor","year":"2009","unstructured":"Taylor, D. R. et al. Role of ADAMs in the ectodomain shedding and conformational conversion of the prion protein. Journal of Biological Chemistry 284, 22590\u201322600 (2009).","journal-title":"Journal of Biological Chemistry"},{"key":"49482_CR54","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s13024-018-0248-6","volume":"13","author":"L Linsenmeier","year":"2018","unstructured":"Linsenmeier, L. et al. Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein. Mol Neurodegener 13, 18, https:\/\/doi.org\/10.1186\/s13024-018-0248-6 (2018).","journal-title":"Mol Neurodegener"},{"key":"49482_CR55","doi-asserted-by":"publisher","first-page":"3145","DOI":"10.1074\/jbc.M115.703058","volume":"291","author":"PJ Noy","year":"2016","unstructured":"Noy, P. J. et al. TspanC8 Tetraspanins and A Disintegrin and Metalloprotease 10 (ADAM10) Interact via Their Extracellular Regions: EVIDENCE FOR DISTINCT BINDING MECHANISMS FOR DIFFERENT TspanC8 PROTEINS. J Biol Chem 291, 3145\u20133157, https:\/\/doi.org\/10.1074\/jbc.M115.703058 (2016).","journal-title":"J Biol Chem"},{"key":"49482_CR56","doi-asserted-by":"publisher","first-page":"7756","DOI":"10.1167\/iovs.13-13088","volume":"54","author":"L De Groef","year":"2013","unstructured":"De Groef, L., Van Hove, I., Dekeyster, E., Stalmans, I. & Moons, L. MMPs in the trabecular meshwork: promising targets for future glaucoma therapies? Investigative ophthalmology & visual science 54, 7756\u20137763 (2013).","journal-title":"Investigative ophthalmology & visual science"},{"key":"49482_CR57","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1242\/jcs.043604","volume":"122","author":"CL Haigh","year":"2009","unstructured":"Haigh, C. L. et al. Dominant roles of the polybasic proline motif and copper in the PrP23-89-mediated stress protection response. Journal of cell science 122, 1518\u20131528 (2009).","journal-title":"Journal of cell science"},{"key":"49482_CR58","doi-asserted-by":"crossref","unstructured":"Pattabiraman, P. P. & Rao, P. V. Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells. American Journal of Physiology-Cell Physiology (2009).","DOI":"10.1152\/ajpcell.00317.2009"},{"key":"49482_CR59","doi-asserted-by":"publisher","first-page":"3018","DOI":"10.1242\/jcs.165365","volume":"128","author":"DD Richardson","year":"2015","unstructured":"Richardson, D. D. et al. The prion protein inhibits monocytic cell migration by stimulating beta1 integrin adhesion and uropod formation. J Cell Sci 128, 3018\u20133029, https:\/\/doi.org\/10.1242\/jcs.165365 (2015).","journal-title":"J Cell Sci"},{"key":"49482_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08110-x","volume":"7","author":"J Ezpeleta","year":"2017","unstructured":"Ezpeleta, J. et al. Protective role of cellular prion protein against TNF\u03b1-mediated inflammation through TACE \u03b1-secretase. Scientific reports 7, 7671 (2017).","journal-title":"Scientific reports"},{"key":"49482_CR61","first-page":"1","volume":"5","author":"A Alleaume-Butaux","year":"2013","unstructured":"Alleaume-Butaux, A. et al. Cellular prion protein is required for neuritogenesis: fine-tuning of multiple singaling pathways involved in focal adhesions and actin cytoskeleton dynamics. Cell Health and Cytoskeleton 5, 1\u201312 (2013).","journal-title":"Cell Health and Cytoskeleton"},{"key":"49482_CR62","doi-asserted-by":"publisher","first-page":"3309","DOI":"10.1167\/iovs.12-11362","volume":"54","author":"D-J Oh","year":"2013","unstructured":"Oh, D.-J. et al. Overexpression of SPARC in Human Trabecular Meshwork Increases Intraocular Pressure and Alters Extracellular MatrixSPARC Overexpression Increases IOP and TM ECM. Investigative ophthalmology & visual science 54, 3309\u20133319, https:\/\/doi.org\/10.1167\/iovs.12-11362 (2013).","journal-title":"Investigative ophthalmology & visual science"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49482-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49482-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49482-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T13:26:41Z","timestamp":1671283601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49482-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,11]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["49482"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-49482-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,11]]},"assertion":[{"value":"21 March 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 August 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"13090"}}