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

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.