Human wild‐type and D76N β2‐microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-11-01
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| Series: | FASEB BioAdvances |
| Subjects: | |
| Online Access: | https://doi.org/10.1096/fba.2023-00073 |
| _version_ | 1797635965644177408 |
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| author | Sara Raimondi Giulia Faravelli Paola Nocerino Valentina Mondani Alma Baruffaldi Loredana Marchese Maria Chiara Mimmi Diana Canetti Guglielmo Verona Marianna Caterino Margherita Ruoppolo P. Patrizia Mangione Vittorio Bellotti Francesca Lavatelli Sofia Giorgetti |
| author_facet | Sara Raimondi Giulia Faravelli Paola Nocerino Valentina Mondani Alma Baruffaldi Loredana Marchese Maria Chiara Mimmi Diana Canetti Guglielmo Verona Marianna Caterino Margherita Ruoppolo P. Patrizia Mangione Vittorio Bellotti Francesca Lavatelli Sofia Giorgetti |
| author_sort | Sara Raimondi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:28:05Z |
| format | Article |
| id | doaj.art-5149cb901be64b8ea5200c5f776cb102 |
| institution | Directory Open Access Journal |
| issn | 2573-9832 |
| language | English |
| last_indexed | 2024-03-11T12:28:05Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | FASEB BioAdvances |
| spelling | doaj.art-5149cb901be64b8ea5200c5f776cb1022023-11-06T06:21:11ZengWileyFASEB BioAdvances2573-98322023-11-0151148450510.1096/fba.2023-00073Human wild‐type and D76N β2‐microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegansSara Raimondi0Giulia Faravelli1Paola Nocerino2Valentina Mondani3Alma Baruffaldi4Loredana Marchese5Maria Chiara Mimmi6Diana Canetti7Guglielmo Verona8Marianna Caterino9Margherita Ruoppolo10P. Patrizia Mangione11Vittorio Bellotti12Francesca Lavatelli13Sofia Giorgetti14Department of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyDepartment of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyDepartment of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyDepartment of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyDepartment of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyDepartment of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyDepartment of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyCentre for Amyloidosis, Division of Medicine University College London London UKDepartment of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyDepartment of Molecular Medicine and Medical Biotechnology University of Naples "Federico II" Naples ItalyDepartment of Molecular Medicine and Medical Biotechnology University of Naples "Federico II" Naples ItalyDepartment of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyResearch Department Fondazione IRCCS Policlinico San Matteo Pavia ItalyDepartment of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyDepartment of Molecular Medicine, Institute of Biochemistry University of Pavia Pavia ItalyAbstract 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.https://doi.org/10.1096/fba.2023-00073C. elegansintegrated omicsmisfoldingproteotoxicitysystemic amyloidosisβ2‐microglobulin |
| spellingShingle | Sara Raimondi Giulia Faravelli Paola Nocerino Valentina Mondani Alma Baruffaldi Loredana Marchese Maria Chiara Mimmi Diana Canetti Guglielmo Verona Marianna Caterino Margherita Ruoppolo P. Patrizia Mangione Vittorio Bellotti Francesca Lavatelli Sofia Giorgetti Human wild‐type and D76N β2‐microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans FASEB BioAdvances C. elegans integrated omics misfolding proteotoxicity systemic amyloidosis β2‐microglobulin |
| title | Human wild‐type and D76N β2‐microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans |
| title_full | Human wild‐type and D76N β2‐microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans |
| title_fullStr | Human wild‐type and D76N β2‐microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans |
| title_full_unstemmed | Human wild‐type and D76N β2‐microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans |
| title_short | Human wild‐type and D76N β2‐microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans |
| title_sort | human wild type and d76n β2 microglobulin variants are significant proteotoxic and metabolic stressors for transgenic c elegans |
| topic | C. elegans integrated omics misfolding proteotoxicity systemic amyloidosis β2‐microglobulin |
| url | https://doi.org/10.1096/fba.2023-00073 |
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