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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.

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