Human wild-type and D76N β 2 -microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans .

Autor:	Raimondi S; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy., Faravelli G; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy., Nocerino P; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy., Mondani V; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy., Baruffaldi A; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy., Marchese L; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy.; Research Department Fondazione IRCCS Policlinico San Matteo Pavia Italy., Mimmi MC; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy., Canetti D; Centre for Amyloidosis, Division of Medicine University College London London UK., Verona G; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy.; Centre for Amyloidosis, Division of Medicine University College London London UK., Caterino M; Department of Molecular Medicine and Medical Biotechnology University of Naples 'Federico II' Naples Italy.; CEINGE - Biotecnologie Avanzate s.c.a.r.l. Naples Italy., Ruoppolo M; Department of Molecular Medicine and Medical Biotechnology University of Naples 'Federico II' Naples Italy.; CEINGE - Biotecnologie Avanzate s.c.a.r.l. Naples Italy., Mangione PP; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy.; Research Department Fondazione IRCCS Policlinico San Matteo Pavia Italy., Bellotti V; Research Department Fondazione IRCCS Policlinico San Matteo Pavia Italy., Lavatelli F; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy.; Research Department Fondazione IRCCS Policlinico San Matteo Pavia Italy., Giorgetti S; Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia Italy.; Research Department Fondazione IRCCS Policlinico San Matteo Pavia Italy.
Jazyk:	angličtina
Zdroj:	FASEB bioAdvances [FASEB Bioadv] 2023 Oct 25; Vol. 5 (11), pp. 484-505. Date of Electronic Publication: 2023 Oct 25 (Print Publication: 2023).
DOI:	10.1096/fba.2023-00073
Abstrakt:	β 2 -microglobulin (β 2 -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 β 2 -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 β 2 -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 β 2 -m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with β 2 -m levels rather than with the presence of mutations, being more pronounced in WT β 2 -m worms. β 2 -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 β 2 -m at high concentration compared to D76N β 2 -m worms. Altogether, these data show that β 2 -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 β 2 -m amyloidosis (high levels of non-mutated β 2 -m vs. normal levels of variant β 2 -m) and provide important clues on the molecular bases of these human diseases. Competing Interests: The authors declare no conflicts of interest. (©2023 The Authors FASEB BioAdvances published by The Federation of American Societies for Experimental Biology.)
Databáze:	MEDLINE
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