Amyloid Disease Models in C. elegans: insights into the toxicity of B2-microglobulin and islet amyloid polypeptide

The formation of amyloid fibres is associated with degenerative disorders including Alzheimer’s, type II diabetes mellitus (T2DM) and dialysis related amyloidosis (DRA) amongst others. In order to study how amyloidogenic proteins can aggregate and cause toxicity, numerous in vivo disease models have been generated in the roundworm nematode Caenorhabditis elegans. Although many amyloid disease models for neurodegenerative disorders have been generated, models for systemic disorders such as T2DM and DRA are lacking. To address this, novel models of T2DM and DRA were generated to express variants of either IAPP (hIAPP, S20G IAPP or rat IAPP) or B2-microglobulin (WT B2m, D76N B2m or DN6 B2m). A range of behavioural phenotypes were explored in these models, including motility, development, lifespan, thermotolerance and ER stress. Disease models expressing IAPP or B2m variants with high amyloidogenic aggregation propensity in vitro (S20G IAPP, D76N B2m and DN6 B2m) also confer to toxic phenotypes in the nematodes. C. elegans expressing variants that do not produce amyloid fibres under physiological conditions in vitro (WT B2m and rat IAPP) displayed low toxicity. Furthermore, the role of the proteostasis network was explored in C. elegans disease models expressing amyloidogenic proteins. The role of HSP-90 in modulating amyloid-B toxicity was confirmed in an Alzheimer’s disease strain, both cell-autonomously and cell-nonautonomously. Taken together, the results presented here demonstrate the utility of C. elegans in understanding the toxicity and aggregation of amyloid proteins; and present a platform on which future research studies on IAPP and B2m can be built upon.