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

beta(2)-microglobulin (beta(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 beta(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 beta(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 beta(2)-m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with beta(2)-m levels rather than with the presence of mutations, being more pronounced in WT beta(2)-m worms. beta(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 beta(2)-m at high concentration compared to D76N beta(2)-m worms. Altogether, these data show that beta(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 beta(2)-m amyloidosis (high levels of non-mutated beta(2)-m vs. normal levels of variant beta(2)-m) and provide important clues on the molecular bases of these human diseases.