eprintid: 10180232 rev_number: 6 eprint_status: archive userid: 699 dir: disk0/10/18/02/32 datestamp: 2023-11-06 15:19:17 lastmod: 2023-11-06 15:19:17 status_changed: 2023-11-06 15:19:17 type: article metadata_visibility: show sword_depositor: 699 creators_name: Raimondi, S creators_name: Faravelli, G creators_name: Nocerino, P creators_name: Mondani, V creators_name: Baruffaldi, A creators_name: Marchese, L creators_name: Mimmi, MC creators_name: Canetti, D creators_name: Verona, G creators_name: Caterino, M creators_name: Ruoppolo, M creators_name: Mangione, PP creators_name: Bellotti, V creators_name: Lavatelli, F creators_name: Giorgetti, S title: Human wild-type and D76N β_{2}-microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans ispublished: pub divisions: UCL divisions: B02 divisions: C10 divisions: D17 divisions: G90 note: © 2023 The Authors FASEB BioAdvances published by The Federation of American Societies for Experimental Biology. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). abstract: β2-microglobulin (β2-m) 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-type (WT) protein in hemodialyzed patients, or in presence of mutations, such as D76N β2-m, which favor protein deposition in the adulthood, despite normal plasma levels. Here we describe a new transgenic Caenorhabditis elegans (C. elegans) strain expressing human WT β2-m at high concentrations, mimicking the condition that underlies dialysis-related amyloidosis (DRA) and we compare it to a previously established strain expressing the highly amyloidogenic D76N β2-m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with β2-m levels rather than with the presence of mutations, being more pronounced in WT β2-m worms. β2-m 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 β2-m at high concentration compared to D76N β2-m worms. Altogether, these data show that β2-m is a proteotoxic protein in vivo also in its wild-type form, and that concentration plays a key role in modulating pathogenicity. Our transgenic nematodes recapitulate the distinctive features subtending DRA compared to hereditary β2-m amyloidosis (high levels of non-mutated β2-m vs. normal levels of variant β2-m) and provide important clues on the molecular bases of these human diseases. date: 2023-11 date_type: published publisher: Wiley official_url: https://doi.org/10.1096/fba.2023-00073 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2102987 doi: 10.1096/fba.2023-00073 lyricists_name: Verona, Guglielmo lyricists_name: Bellotti, Vittorio lyricists_name: Canetti, Diana lyricists_id: GVERO54 lyricists_id: VBELL78 lyricists_id: DCANE19 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: FASEB BioAdvances volume: 5 number: 11 pagerange: 484-505 citation: Raimondi, S; Faravelli, G; Nocerino, P; Mondani, V; Baruffaldi, A; Marchese, L; Mimmi, MC; ... Giorgetti, S; + view all <#> Raimondi, S; Faravelli, G; Nocerino, P; Mondani, V; Baruffaldi, A; Marchese, L; Mimmi, MC; Canetti, D; Verona, G; Caterino, M; Ruoppolo, M; Mangione, PP; Bellotti, V; Lavatelli, F; Giorgetti, S; - view fewer <#> (2023) Human wild-type and D76N β_{2}-microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans. FASEB BioAdvances , 5 (11) pp. 484-505. 10.1096/fba.2023-00073 <https://doi.org/10.1096/fba.2023-00073>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10180232/1/Human%20wild%20type%20and%20D76N%20%202%20microglobulin%20variants%20are%20significant%20proteotoxic.pdf