{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T02:55:05Z","timestamp":1793933705110,"version":"4.8.0"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,11,15]],"date-time":"2017-11-15T00:00:00Z","timestamp":1510704000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,11,15]],"date-time":"2017-11-15T00:00:00Z","timestamp":1510704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    AL amyloidosis is characterized by widespread deposition of immunoglobulin light chains (LCs) as amyloid fibrils. Cardiac involvement is frequent and leads to life-threatening cardiomyopathy. Besides the tissue alteration caused by fibrils, clinical and experimental evidence indicates that cardiac damage is also caused by proteotoxicity of prefibrillar amyloidogenic species. As in other amyloidoses, the damage mechanisms at cellular level are complex and largely undefined. We have characterized the molecular changes in primary human cardiac fibroblasts (hCFs) exposed\n                    <jats:italic>in vitro<\/jats:italic>\n                    to soluble amyloidogenic cardiotoxic LCs from AL cardiomyopathy patients. To evaluate proteome alterations caused by a representative cardiotropic LC, we combined gel-based with label-free shotgun analysis and performed bioinformatics and data validation studies. To assess the generalizability of our results we explored the effects of multiple LCs on hCF viability and on levels of a subset of cellular proteins. Our results indicate that exposure of hCFs to cardiotropic LCs translates into proteome remodeling, associated with apoptosis activation and oxidative stress. The proteome alterations affect proteins involved in cytoskeletal organization, protein synthesis and quality control, mitochondrial activity and metabolism, signal transduction and molecular trafficking. These results support and expand the concept that soluble amyloidogenic cardiotropic LCs exert toxic effects on cardiac cells.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-15424-3","type":"journal-article","created":{"date-parts":[[2017,11,9]],"date-time":"2017-11-09T09:56:24Z","timestamp":1510221384000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":99,"title":["Proteotoxicity in cardiac amyloidosis: amyloidogenic light chains affect the levels of intracellular proteins in human heart cells"],"prefix":"10.1038","volume":"7","author":[{"given":"Esther","family":"Imperlini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Gnecchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Rognoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"Sabid\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Chiara","family":"Ciuffreda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5994-5138","authenticated-orcid":false,"given":"Giovanni","family":"Palladini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guadalupe","family":"Espadas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco Mattia","family":"Mancuso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Bozzola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Malpasso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Valentini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Palladini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Orr\u00f9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Ferraro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Milani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Perlini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Salvatore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giampaolo","family":"Merlini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Lavatelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,15]]},"reference":[{"key":"15424_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1080\/13506129.2016.1257986","volume":"23","author":"JD Sipe","year":"2016","unstructured":"Sipe, J. D. et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid 23, 209\u201313 (2016).","journal-title":"Amyloid"},{"key":"15424_CR2","doi-asserted-by":"publisher","first-page":"5124","DOI":"10.1182\/blood-2013-01-453001","volume":"121","author":"G Merlini","year":"2013","unstructured":"Merlini, G., Wechalekar, A. D. & Palladini, G. Systemic light chain amyloidosis: an update for treating physicians. Blood 121, 5124\u20135130 (2013).","journal-title":"Blood"},{"key":"15424_CR3","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.3324\/haematol.2013.094482","volume":"98","author":"G Merlini","year":"2013","unstructured":"Merlini, G. & Palladini, G. Light chain amyloidosis: the heart of the problem. Haematologica 98, 1492\u20131495 (2013).","journal-title":"Haematologica"},{"key":"15424_CR4","first-page":"294","volume":"31","author":"V Sapp","year":"2016","unstructured":"Sapp, V., Jain, M. & Liao, R. Viewing extrinsic proteotoxic stress through the lens of amyloid cardiomyopathy. Physiology (Bethesda) 31, 294\u2013299 (2016).","journal-title":"Physiology (Bethesda)"},{"key":"15424_CR5","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1515\/cclm-2014-0235","volume":"52","author":"F Lavatelli","year":"2014","unstructured":"Lavatelli, F., Albertini, R., Di Fonzo, A., Palladini, G. & Merlini, G. Biochemical markers in early diagnosis and management of systemic amyloidoses. Clin Chem Lab Med 52, 1517\u20131531 (2014).","journal-title":"Clin Chem Lab Med"},{"key":"15424_CR6","doi-asserted-by":"publisher","first-page":"1979","DOI":"10.1038\/leu.2016.191","volume":"30","author":"G Merlini","year":"2016","unstructured":"Merlini, G. et al. Rationale, application, and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis. Leukemia 30, 1979\u20131986 (2016).","journal-title":"Leukemia"},{"key":"15424_CR7","doi-asserted-by":"publisher","first-page":"3854","DOI":"10.1182\/blood-2005-11-4385","volume":"107","author":"G Palladini","year":"2006","unstructured":"Palladini, G. et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. Blood 107, 3854\u20133858 (2006).","journal-title":"Blood"},{"key":"15424_CR8","doi-asserted-by":"publisher","first-page":"4541","DOI":"10.1200\/JCO.2011.37.7614","volume":"30","author":"G Palladini","year":"2012","unstructured":"Palladini, G. et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 30, 4541\u20134549 (2012).","journal-title":"J Clin Oncol"},{"key":"15424_CR9","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.15252\/emmm.201404190","volume":"6","author":"J Guan","year":"2014","unstructured":"Guan, J. et al. Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity. EMBO Mol Med 6, 1493\u20131507 (2014).","journal-title":"EMBO Mol Med"},{"key":"15424_CR10","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1007\/s00395-013-0378-5","volume":"108","author":"J Guan","year":"2013","unstructured":"Guan, J. et al. Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity. Basic Res Cardiol 108, 378 (2013).","journal-title":"Basic Res Cardiol"},{"key":"15424_CR11","doi-asserted-by":"publisher","first-page":"H95","DOI":"10.1152\/ajpheart.00186.2013","volume":"305","author":"S Mishra","year":"2013","unstructured":"Mishra, S. et al. Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish. Am J Physiol Heart Circ Physiol 305, H95\u2013103 (2013).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"15424_CR12","doi-asserted-by":"publisher","first-page":"4188","DOI":"10.1073\/pnas.0912263107","volume":"107","author":"J Shi","year":"2010","unstructured":"Shi, J. et al. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway. Proc Natl Acad Sci USA 107, 4188\u20134193 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"15424_CR13","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1161\/01.RES.0000126569.75419.74","volume":"94","author":"DA Brenner","year":"2004","unstructured":"Brenner, D. A. et al. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ Res 94, 1008\u20131010 (2004).","journal-title":"Circ Res"},{"key":"15424_CR14","doi-asserted-by":"publisher","first-page":"3543","DOI":"10.1182\/blood-2013-10-525634","volume":"123","author":"L Diomede","year":"2014","unstructured":"Diomede, L. et al. A Caenorhabditis elegans-based assay recognizes immunoglobulin light chains causing heart amyloidosis. Blood 123, 3543\u201352 (2014).","journal-title":"Blood"},{"key":"15424_CR15","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.2353\/ajpath.2006.060183","volume":"169","author":"GF Monis","year":"2006","unstructured":"Monis, G. F. et al. Role of endocytic inhibitory drugs on internalization of amyloidogenic light chains by cardiac fibroblasts. Am J Pathol 169, 1939\u20131952 (2006).","journal-title":"Am J Pathol"},{"key":"15424_CR16","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/S0002-9440(10)62244-4","volume":"166","author":"V Trinkaus-Randall","year":"2005","unstructured":"Trinkaus-Randall, V. et al. Cellular response of cardiac fibroblasts to amyloidogenic light chains. Am J Pathol 166, 197\u2013208 (2005).","journal-title":"Am J Pathol"},{"key":"15424_CR17","doi-asserted-by":"publisher","first-page":"4614","DOI":"10.1096\/fj.15-272179","volume":"29","author":"F Lavatelli","year":"2015","unstructured":"Lavatelli, F. et al. Novel mitochondrial protein interactors of immunoglobulin light chains causing heart amyloidosis. FASEB J 29, 4614\u201328 (2015).","journal-title":"FASEB J"},{"key":"15424_CR18","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1161\/circ.104.14.1594","volume":"104","author":"R Liao","year":"2001","unstructured":"Liao, R. et al. Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation 104, 1594\u20131597 (2001).","journal-title":"Circulation"},{"key":"15424_CR19","doi-asserted-by":"publisher","first-page":"19813","DOI":"10.1074\/jbc.M116.736736","volume":"291","author":"M Marin-Argany","year":"2016","unstructured":"Marin-Argany, M. et al. Cell Damage in Light Chain Amyloidosis: fibril internalization, toxicity and cell-mediated seeding. J Biol Chem 291, 19813\u201319825 (2016).","journal-title":"J Biol Chem"},{"key":"15424_CR20","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.pharmthera.2009.05.002","volume":"123","author":"KE Porter","year":"2009","unstructured":"Porter, K. E. & Turner, N. A. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 123, 255\u2013278 (2009).","journal-title":"Pharmacol Ther"},{"key":"15424_CR21","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1161\/01.CIR.0000085658.98621.49","volume":"108","author":"BI Jugdutt","year":"2003","unstructured":"Jugdutt, B. I. Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation 108, 1395\u20131403 (2003).","journal-title":"Circulation"},{"key":"15424_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2010.75","volume":"1","author":"LA Sikkink","year":"2010","unstructured":"Sikkink, L. A. & Ramirez-Alvarado, M. Cytotoxicity of amyloidogenic immunoglobulin light chains in cell culture. Cell Death Dis 1, e98 (2010).","journal-title":"Cell Death Dis"},{"key":"15424_CR23","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1074\/mcp.M113.028027","volume":"12","author":"DA Megger","year":"2013","unstructured":"Megger, D. A. et al. Proteomic differences between hepatocellular carcinoma and nontumorous liver tissue investigated by a combined gel-based and label-free quantitative proteomics study. Mol Cell Proteomics 12, 2006\u20132020 (2013).","journal-title":"Mol Cell Proteomics"},{"key":"15424_CR24","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.ijcard.2009.04.044","volume":"145","author":"RQ Migrino","year":"2010","unstructured":"Migrino, R. Q. et al. Systemic and microvascular oxidative stress induced by light chain amyloidosis. Int J Cardiol 145, 67\u201368 (2010).","journal-title":"Int J Cardiol"},{"key":"15424_CR25","doi-asserted-by":"publisher","unstructured":"Diomede, L. et al. Cardiac light chain amyloidosis: The role of metal ions in oxidative stress and mitochondrial damage. Antioxid Redox Signal, https:\/\/doi.org\/10.1089\/ars.2016.6848 (2017).","DOI":"10.1089\/ars.2016.6848"},{"key":"15424_CR26","first-page":"541","volume":"22","author":"Q Yao","year":"2009","unstructured":"Yao, Q., Qu, X., Yang, Q., Wei, M. & Kong, B. CLIC4 mediates TGF-beta1-induced fibroblast-to-myofibroblast transdifferentiation in ovarian cancer. Oncol Rep 22, 541\u20138 (2009).","journal-title":"Oncol Rep"},{"key":"15424_CR27","doi-asserted-by":"publisher","first-page":"34202","DOI":"10.1074\/jbc.M112.384032","volume":"287","author":"ML Hegde","year":"2012","unstructured":"Hegde, M. L. et al. Enhancement of NEIL1 protein-initiated oxidized DNA base excision repair by heterogeneous nuclear ribonucleoprotein U (hnRNP-U) via direct interaction. J Biol Chem 287, 34202\u201311 (2012).","journal-title":"J Biol Chem"},{"key":"15424_CR28","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.freeradbiomed.2012.11.010","volume":"56","author":"S Singh","year":"2013","unstructured":"Singh, S. et al. Aldehyde dehydrogenases in cellular responses to oxidative\/electrophilic stress. Free Radic Biol Med 56, 89\u2013101 (2013).","journal-title":"Free Radic Biol Med"},{"key":"15424_CR29","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1016\/j.bbadis.2013.09.015","volume":"1842","author":"AM Swomley","year":"2014","unstructured":"Swomley, A. M. et al. Abeta, oxidative stress in Alzheimer disease: evidence based on proteomics studies. Biochim Biophys Acta 1842, 1248\u20131257 (2014).","journal-title":"Biochim Biophys Acta"},{"key":"15424_CR30","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1042\/bj20031208","volume":"379","author":"HY Baek","year":"2004","unstructured":"Baek, H. Y. et al. Oxidative-stress-related proteome changes in Helicobacter pylori-infected human gastric mucosa. Biochem J 379, 291\u2013299 (2004).","journal-title":"Biochem J"},{"key":"15424_CR31","doi-asserted-by":"publisher","first-page":"573208","DOI":"10.1155\/2014\/573208","volume":"2014","author":"D Ortu\u00f1o-Sahag\u00fan","year":"2014","unstructured":"Ortu\u00f1o-Sahag\u00fan, D., Pall\u00e0s, M. & Rojas-Mayorqu\u00edn, A. E. Oxidative stress in aging: advances in proteomic approaches. Oxid Med Cell Longev 2014, 573208 (2014).","journal-title":"Oxid Med Cell Longev"},{"key":"15424_CR32","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.1016\/j.freeradbiomed.2011.06.032","volume":"51","author":"MA Baraibar","year":"2011","unstructured":"Baraibar, M. A. et al. Oxidative stress-induced proteome alterations target different cellular pathways in human myoblasts. Free Radic Biol Med 51, 1522\u201332 (2011).","journal-title":"Free Radic Biol Med"},{"issue":"M111","key":"15424_CR33","first-page":"010447","volume":"11","author":"M\u00d8 Arntzen","year":"2012","unstructured":"Arntzen, M. \u00d8. & Thiede, B. ApoptoProteomics, an integrated database for analysis of proteomics data obtained from apoptotic cells. Mol Cell Proteomics 11(M111), 010447 (2012).","journal-title":"Mol Cell Proteomics"},{"key":"15424_CR34","doi-asserted-by":"publisher","first-page":"5642","DOI":"10.1021\/pr400583h","volume":"12","author":"F Brambilla","year":"2013","unstructured":"Brambilla, F. et al. Shotgun protein profile of human adipose tissue and its changes in relation to systemic amyloidoses. J Proteome Res 12, 5642\u20135655 (2013).","journal-title":"J Proteome Res"},{"issue":"Pt 10","key":"15424_CR35","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1242\/jcs.108.10.3317","volume":"108","author":"C Albig\u00e8s-Rizo","year":"1995","unstructured":"Albig\u00e8s-Rizo, C., Frachet, P. & Block, M. R. Down regulation of talin alters cell adhesion and the processing of the alpha 5 beta 1 integrin. J Cell Sci 108(Pt 10), 3317\u20133329 (1995).","journal-title":"J Cell Sci"},{"key":"15424_CR36","doi-asserted-by":"publisher","first-page":"e0131238","DOI":"10.1371\/journal.pone.0131238","volume":"10","author":"S Bogatan","year":"2015","unstructured":"Bogatan, S. et al. Talin is required continuously for cardiomyocyte remodeling during heart growth in Drosophila. PLoS One 10, e0131238 (2015).","journal-title":"PLoS One"},{"key":"15424_CR37","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1089\/dna.1995.14.689","volume":"14","author":"G Schevzov","year":"1995","unstructured":"Schevzov, G., Lloyd, C. & Gunning, P. Impact of altered actin gene expression on vinculin, talin, cell spreading, and motility. DNA Cell Biol 14, 689\u2013700 (1995).","journal-title":"DNA Cell Biol"},{"key":"15424_CR38","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1089\/dna.2010.1128","volume":"30","author":"L Varisli","year":"2011","unstructured":"Varisli, L. et al. Ubiquitously expressed hematological and neurological expressed 1 downregulates Akt-mediated GSK3\u03b2 signaling, and its knockdown results in deregulated G2\/M transition in prostate cells. DNA Cell Biol 30, 419\u2013429 (2011).","journal-title":"DNA Cell Biol"},{"key":"15424_CR39","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/s004410050795","volume":"288","author":"A Agocha","year":"1997","unstructured":"Agocha, A., Sigel, A. V. & Eghbali-Webb, M. Characterization of adult human heart fibroblasts in culture: a comparative study of growth, proliferation and collagen production in human and rabbit cardiac fibroblasts and their response to transforming growth factor-beta1. Cell Tissue Res 288, 87\u201393 (1997).","journal-title":"Cell Tissue Res"},{"key":"15424_CR40","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1097\/FJC.0b013e3182137e17","volume":"57","author":"S Rohr","year":"2011","unstructured":"Rohr, S. Cardiac fibroblasts in cell culture systems: myofibroblasts all along? J Cardiovasc Pharmacol 57, 389\u2013399 (2011).","journal-title":"J Cardiovasc Pharmacol"},{"key":"15424_CR41","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1074\/mcp.M700545-MCP200","volume":"7","author":"F Lavatelli","year":"2008","unstructured":"Lavatelli, F. et al. Amyloidogenic and associated proteins in systemic amyloidosis proteome of adipose tissue. Mol Cell Proteomics 7, 1570\u20131583 (2008).","journal-title":"Mol Cell Proteomics"},{"key":"15424_CR42","doi-asserted-by":"publisher","first-page":"638083","DOI":"10.1155\/2013\/638083","volume":"2013","author":"K Cuanalo-Contreras","year":"2013","unstructured":"Cuanalo-Contreras, K., Mukherjee, A. & Soto, C. Role of protein misfolding and proteostasis deficiency in protein misfolding diseases and aging. Int J Cell Biol 2013, 638083 (2013).","journal-title":"Int J Cell Biol"},{"key":"15424_CR43","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1258\/ebm.2010.010327","volume":"236","author":"BM Riederer","year":"2011","unstructured":"Riederer, B. M., Leuba, G., Vernay, A. & Riederer, I. M. The role of the ubiquitin proteasome system in Alzheimer\u2019s disease. Exp Biol Med (Maywood) 236, 268\u2013276 (2011).","journal-title":"Exp Biol Med (Maywood)"},{"key":"15424_CR44","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.bbadis.2009.10.006","volume":"1802","author":"PI Moreira","year":"2010","unstructured":"Moreira, P. I., Carvalho, C., Zhu, X., Smith, M. A. & Perry, G. Mitochondrial dysfunction is a trigger of Alzheimer\u2019s disease pathophysiology. Biochim Biophys Acta 1802, 2\u201310 (2010).","journal-title":"Biochim Biophys Acta"},{"key":"15424_CR45","doi-asserted-by":"publisher","first-page":"206","DOI":"10.3389\/fphar.2015.00206","volume":"6","author":"A Kumar","year":"2015","unstructured":"Kumar, A. & Singh, A. A review on mitochondrial restorative mechanism of antioxidants in Alzheimer\u2019s disease and other neurological conditions. Front Pharmacol 6, 206 (2015).","journal-title":"Front Pharmacol"},{"key":"15424_CR46","doi-asserted-by":"crossref","first-page":"925050","DOI":"10.4061\/2011\/925050","volume":"2011","author":"L Pagani","year":"2011","unstructured":"Pagani, L. & Eckert, A. Amyloid-Beta interaction with mitochondria. Int J Alzheimers Dis 2011, 925050 (2011).","journal-title":"Int J Alzheimers Dis"},{"key":"15424_CR47","doi-asserted-by":"publisher","first-page":"e01684","DOI":"10.7554\/eLife.01684","volume":"3","author":"ME Harner","year":"2014","unstructured":"Harner, M. E. et al. Aim24 and MICOS modulate respiratory function, tafazzin-related cardiolipin modification and mitochondrial architecture. Elife 3, e01684 (2014).","journal-title":"Elife"},{"key":"15424_CR48","doi-asserted-by":"publisher","first-page":"4356","DOI":"10.1038\/emboj.2011.379","volume":"30","author":"M Harner","year":"2011","unstructured":"Harner, M. et al. The mitochondrial contact site complex, a determinant of mitochondrial architecture. EMBO J 30, 4356\u20134370 (2011).","journal-title":"EMBO J"},{"key":"15424_CR49","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1261\/rna.1132008","volume":"14","author":"S Robledo","year":"2008","unstructured":"Robledo, S. et al. The role of human ribosomal proteins in the maturation of rRNA and ribosome production. RNA 14, 1918\u20131929 (2008).","journal-title":"RNA"},{"key":"15424_CR50","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1002\/med.21327","volume":"35","author":"W Wang","year":"2015","unstructured":"Wang, W. et al. Ribosomal proteins and human diseases: pathogenesis, molecular mechanisms, and therapeutic implications. Med Res Rev 35, 225\u2013285 (2015).","journal-title":"Med Res Rev"},{"key":"15424_CR51","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1016\/j.febslet.2014.03.024","volume":"588","author":"J Armistead","year":"2014","unstructured":"Armistead, J. & Triggs-Raine, B. Diverse diseases from a ubiquitous process: the ribosomopathy paradox. FEBS Lett 588, 1491\u20131500 (2014).","journal-title":"FEBS Lett"},{"key":"15424_CR52","doi-asserted-by":"publisher","first-page":"9171","DOI":"10.1523\/JNEUROSCI.3040-05.2005","volume":"25","author":"Q Ding","year":"2005","unstructured":"Ding, Q., Markesbery, W. R., Chen, Q., Li, F. & Keller, J. N. Ribosome dysfunction is an early event in Alzheimer\u2019s disease. J Neurosci 25, 9171\u20139175 (2005).","journal-title":"J Neurosci"},{"key":"15424_CR53","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.tibs.2013.09.003","volume":"38","author":"MY Sherman","year":"2013","unstructured":"Sherman, M. Y. & Qian, S. B. Less is more: improving proteostasis by translation slow down. Trends Biochem Sci 38, 585\u2013591 (2013).","journal-title":"Trends Biochem Sci"},{"key":"15424_CR54","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.biocel.2008.02.011","volume":"41","author":"SJ Assinder","year":"2009","unstructured":"Assinder, S. J., Stanton, J. A. & Prasad, P. D. Transgelin: an actin-binding protein and tumour suppressor. Int J Biochem Cell Biol 41, 482\u2013486 (2009).","journal-title":"Int J Biochem Cell Biol"},{"key":"15424_CR55","doi-asserted-by":"publisher","first-page":"e005868","DOI":"10.1161\/JAHA.112.005868","volume":"2","author":"K Tanaka","year":"2013","unstructured":"Tanaka, K. et al. Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases in cardiac amyloidosis. J Am Heart Assoc 2, e005868 (2013).","journal-title":"J Am Heart Assoc"},{"key":"15424_CR56","doi-asserted-by":"crossref","first-page":"7910","DOI":"10.1523\/JNEUROSCI.16-24-07910.1996","volume":"16","author":"JR Backstrom","year":"1996","unstructured":"Backstrom, J. R., Lim, G. P., Cullen, M. J. & T\u00f6k\u00e9s, Z. A. Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1\u201340). J Neurosci 16, 7910\u20137919 (1996).","journal-title":"J Neurosci"},{"key":"15424_CR57","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1056\/NEJMra1106180","volume":"368","author":"MS Willis","year":"2013","unstructured":"Willis, M. S. & Patterson, C. Proteotoxicity and cardiac dysfunction\u2013Alzheimer\u2019s disease of the heart? N Engl J Med 368, 455\u2013464 (2013).","journal-title":"N Engl J Med"},{"key":"15424_CR58","doi-asserted-by":"publisher","first-page":"e76022","DOI":"10.1371\/journal.pone.0076022","volume":"8","author":"P Rognoni","year":"2013","unstructured":"Rognoni, P. et al. A Strategy for Synthesis of Pathogenic Human Immunoglobulin Free Light Chains in E. coli. PLoS One 8, e76022 (2013).","journal-title":"PLoS One"},{"key":"15424_CR59","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1002\/ajh.20381","volume":"79","author":"MA Gertz","year":"2005","unstructured":"Gertz, M. A. et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18\u201322 April 2004. Am J Hematol 79, 319\u2013328 (2005).","journal-title":"Am J Hematol"},{"key":"15424_CR60","doi-asserted-by":"publisher","first-page":"4534","DOI":"10.1002\/pmic.200800105","volume":"8","author":"C Pan","year":"2008","unstructured":"Pan, C., Gnad, F., Olsen, J. V. & Mann, M. Quantitative phosphoproteome analysis of a mouse liver cell line reveals specificity of phosphatase inhibitors. Proteomics 8, 4534\u20134546 (2008).","journal-title":"Proteomics"},{"key":"15424_CR61","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1111\/jnc.12683","volume":"129","author":"E Imperlini","year":"2014","unstructured":"Imperlini, E., Orr\u00f9, S., Corbo, C., Daniele, A. & Salvatore, F. Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model. J Neurochem 129, 1002\u201312 (2014).","journal-title":"J Neurochem"},{"key":"15424_CR62","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1002\/pmic.201400242","volume":"15","author":"E Imperlini","year":"2015","unstructured":"Imperlini, E. et al. Synergistic effect of DHT and IGF-1 hyperstimulation in human peripheral blood lymphocytes. Proteomics 15, 1813\u20131818 (2015).","journal-title":"Proteomics"},{"key":"15424_CR63","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1002\/pmic.201200242","volume":"13","author":"M Caterino","year":"2013","unstructured":"Caterino, M. et al. Differential proteomic analysis in human cells subjected to ribosomal stress. Proteomics 13, 1220\u20131227 (2013).","journal-title":"Proteomics"},{"key":"15424_CR64","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1007\/s10545-014-9806-4","volume":"38","author":"M Caterino","year":"2015","unstructured":"Caterino, M. et al. The proteome of cblC defect: in vivo elucidation of altered cellular pathways in humans. J Inherit Metab Dis 38, 969\u201379 (2015).","journal-title":"J Inherit Metab Dis"},{"key":"15424_CR65","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s12931-015-0234-2","volume":"16","author":"E Nigro","year":"2015","unstructured":"Nigro, E. et al. Differentially expressed and activated proteins associated with non small cell lung cancer tissues. Respir Res 16, 74 (2015).","journal-title":"Respir Res"},{"key":"15424_CR66","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1002\/pmic.201300318","volume":"14","author":"S Spaziani","year":"2014","unstructured":"Spaziani, S. et al. Insulin-like growth factor 1 receptor signaling induced by supraphysiological doses of IGF-1 in human peripheral blood lymphocytes. Proteomics 14, 1623\u20131629 (2014).","journal-title":"Proteomics"},{"key":"15424_CR67","doi-asserted-by":"publisher","first-page":"1896","DOI":"10.1038\/nprot.2007.261","volume":"2","author":"J Rappsilber","year":"2007","unstructured":"Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc 2, 1896\u20131906 (2007).","journal-title":"Nat Protoc"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15424-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15424-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15424-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T09:50:57Z","timestamp":1719568257000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15424-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,15]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["15424"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-15424-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,15]]},"assertion":[{"value":"5 January 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 October 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 November 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"15661"}}