Cellular clearance of circulating transthyretin decreases cell-nonautonomous proteotoxicity in <i>Caenorhabditis elegans</i>

Abstract

Significance Evidence suggests that transthyretin (TTR) amyloid diseases result from rate-limiting dissociation of TTR tetramers secreted from the liver into monomers, followed by monomer misfolding and misassembly into a spectrum of aggregates that compromise postmitotic tissue function, including peripheral nerve function. It is unknown how TTR aggregation leads to the demise of neurons cell nonautonomously. Herein we introduce transgenic Caenorhabditis elegans models of TTR amyloidosis that exhibit aggregation and quantifiable cell nonautonomous neuronal phenotypes, including impaired pain sensation, as seen in humans, and altered neuronal morphology. Neuronal dysfunction can be exacerbated by eliminating distal macrophage-like cells that degrade TTR and ameliorated by treating the transgenic worms with TTR RNAi or a TTR kinetic stabilizer, strategies that also delay human polyneuropathy.