Global Proteotoxicity Caused by Human β(2) Microglobulin Variants Impairs the Unfolded Protein Response in C. elegans

Aggregation of β(2) microglobulin (β(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, ΔN6 β(2)m, in haemo-dialysed patients. A second form of familial systemic amyloidosis caused by the β(2)m variant, D76N, results in amyloid deposits in the viscera, without renal dysfunction. Although the folding and misfolding mechanisms of β(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 β(2)m, or the two highly amyloidogenic naturally occurring variants, D76N β(2)m and ΔN6 β(2)m, in the C. elegans bodywall muscle. Nematodes expressing the D76N β(2)m and ΔN6 β(2)m variants exhibit increased age-dependent and cell nonautonomous proteotoxicity associated with reduced motility, delayed development and shortened lifespan. Both β(2)m variants cause widespread endogenous protein aggregation contributing to the increased toxicity in aged animals. We show that expression of β(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 β(2)m variants is reduced, despite the presence of the natural signal sequence, suggesting a possible link between organismal β(2)m toxicity and a disrupted ER secretory metabolism.