Human wild-type and D76N β₂-microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans

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.