Global Proteotoxicity Caused by Human β2 Microglobulin Variants Impairs the Unfolded Protein Response in C. elegans

Aggregation of beta(2) microglobulin (beta(2)m) into amyloid fibrils is associated with systemic amyloidosis, caused by the deposition of amyloid fibrils containing the wild-type protein and its truncated variant, Delta N6 beta(2)m, in haemo-dialysed patients. A second form of familial systemic amyloidosis caused by the beta(2)m variant, D76N, results in amyloid deposits in the viscera, without renal dysfunction. Although the folding and misfolding mechanisms of beta(2) microglobulin have been widely studied in vitro and in vivo, we lack a comparable understanding of the molecular mechanisms underlying toxicity in a cellular and organismal environment. Here, we established transgenic C. elegans lines expressing wild-type (WT) human beta(2)m, or the two highly amyloidogenic naturally occurring variants, D76N beta(2)m and Delta N6 beta(2)m, in the C. elegans bodywall muscle. Nematodes expressing the D76N beta(2)m and Delta N6 beta(2)m variants exhibit increased age-dependent and cell nonautonomous proteotoxicity associated with reduced motility, delayed development and shortened lifespan. Both beta(2)m variants cause widespread endogenous protein aggregation contributing to the increased toxicity in aged animals. We show that expression of beta(2)m reduces the capacity of C. elegans to cope with heat and endoplasmic reticulum (ER) stress, correlating with a deficiency to upregulate BiP/hsp-4 transcripts in response to ER stress in young adult animals. Interestingly, protein secretion in all beta(2)m variants is reduced, despite the presence of the natural signal sequence, suggesting a possible link between organismal beta(2)m toxicity and a disrupted ER secretory metabolism.

Automated summary

Aggregation of beta(2) microglobulin into amyloid fibrils is associated with systemic amyloidosis, with different variants causing distinct pathogenic mechanisms. Expression of beta(2) microglobulin variants in transgenic C. elegans leads to increased proteotoxicity, reduced motility, delayed development, and shortened lifespan, linked to endogenous protein aggregation. Interestingly, all beta(2)m variants exhibit reduced protein secretion, potentially suggesting a disrupted ER secretory metabolism as a link to organismal toxicity.