{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:39:20Z","timestamp":1760575160431,"version":"build-2065373602"},"reference-count":47,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FASEB BioAdvances"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\u03b2<jats:sub>2<\/jats:sub>\u2010microglobulin (\u03b2<jats:sub>2<\/jats:sub>\u2010m) is a plasma protein derived from physiological shedding of the class I major histocompatibility complex (MHCI), causing human systemic amyloidosis either due to persistently high concentrations of the wild\u2010type (WT) protein in hemodialyzed patients, or in presence of mutations, such as D76N \u03b2<jats:sub>2<\/jats:sub>\u2010m, which favor protein deposition in the adulthood, despite normal plasma levels. Here we describe a new transgenic Caenorhabditis elegans (<jats:italic>C. elegans<\/jats:italic>) strain expressing human WT \u03b2<jats:sub>2<\/jats:sub>\u2010m at high concentrations, mimicking the condition that underlies dialysis\u2010related amyloidosis (DRA) and we compare it to a previously established strain expressing the highly amyloidogenic D76N \u03b2<jats:sub>2<\/jats:sub>\u2010m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with \u03b2<jats:sub>2<\/jats:sub>\u2010m levels rather than with the presence of mutations, being more pronounced in WT \u03b2<jats:sub>2<\/jats:sub>\u2010m worms. \u03b2<jats:sub>2<\/jats:sub>\u2010m expression also has a deep impact on the nematodes' proteomic and metabolic profiles. Most significantly affected processes include protein degradation and stress response, amino acids metabolism, and bioenergetics. Molecular alterations are more pronounced in worms expressing WT \u03b2<jats:sub>2<\/jats:sub>\u2010m at high concentration compared to D76N \u03b2<jats:sub>2<\/jats:sub>\u2010m worms. Altogether, these data show that \u03b2<jats:sub>2<\/jats:sub>\u2010m is a proteotoxic protein in\u00a0vivo also in its wild\u2010type form, and that concentration plays a key role in modulating pathogenicity. Our transgenic nematodes recapitulate the distinctive features subtending DRA compared to hereditary \u03b2<jats:sub>2<\/jats:sub>\u2010m amyloidosis (high levels of non\u2010mutated \u03b2<jats:sub>2<\/jats:sub>\u2010m vs. normal levels of variant \u03b2<jats:sub>2<\/jats:sub>\u2010m) and provide important clues on the molecular bases of these human diseases.<\/jats:p>","DOI":"10.1096\/fba.2023-00073","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T09:10:46Z","timestamp":1698225046000},"page":"484-505","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human wild\u2010type and <scp>D76N<\/scp> \u03b2<sub>2<\/sub>\u2010microglobulin variants are significant proteotoxic and metabolic stressors for transgenic <i>C. elegans<\/i>"],"prefix":"10.1096","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3080-8302","authenticated-orcid":false,"given":"Sara","family":"Raimondi","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Institute of Biochemistry University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7348-9404","authenticated-orcid":false,"given":"Giulia","family":"Faravelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Institute of Biochemistry University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5306-808X","authenticated-orcid":false,"given":"Paola","family":"Nocerino","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Institute of Biochemistry University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3161-1176","authenticated-orcid":false,"given":"Valentina","family":"Mondani","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Institute of Biochemistry University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2285-9178","authenticated-orcid":false,"given":"Alma","family":"Baruffaldi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Institute of Biochemistry University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6750-6450","authenticated-orcid":false,"given":"Loredana","family":"Marchese","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Institute of Biochemistry University of Pavia  Pavia Italy"},{"name":"Research Department Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5165-9230","authenticated-orcid":false,"given":"Maria Chiara","family":"Mimmi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Institute of Biochemistry University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5292-8124","authenticated-orcid":false,"given":"Diana","family":"Canetti","sequence":"additional","affiliation":[{"name":"Centre for Amyloidosis, Division of Medicine University College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8100-3876","authenticated-orcid":false,"given":"Guglielmo","family":"Verona","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Institute of Biochemistry University of Pavia  Pavia Italy"},{"name":"Centre for Amyloidosis, Division of Medicine University College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6035-8213","authenticated-orcid":false,"given":"Marianna","family":"Caterino","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology University of Naples \"Federico II\"  Naples Italy"},{"name":"CEINGE \u2013 Biotecnologie Avanzate s.c.a.r.l.  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