Fibroblasts endocytose and degrade transthyretin aggregates in transthyretin-related amyloidosis

Abstract

Transthyretin (TTR)-related amyloidosis is a fatal disorder characterized by systemic extracellular deposition of TTR amyloid fibrils. Mutations in the TTR gene cause an autosomal dominant form of the disease-familial amyloidotic polyneuropathy (FAP). Wild-type (WT) TTR can also form amyloid fibrils in elderly patients with senile systemic amyloidosis. Regression of amyloid deposits in FAP patients who undergo liver transplantation to remove the main source of mutant TTR suggests the existence of mechanisms for the clearance of TTR deposits from the extracellular matrix (ECM), but the precise mechanisms are largely unknown. Because fibroblasts are abundant, playing a central role in the maintenance of the ECM and because the skin is one of the major sites of soluble TTR catabolism, in the present study, we analyzed their role in clearance of TTR aggregates. In vitro studies with a fibroblast cell line revealed that fibroblasts endocytosed and degraded aggregated TTR. Subcutaneous injection of soluble and aggregated TTR into WT mice showed internalization and clearance over time by both fibroblasts and macrophages. Immunohistochemical studies of skin biopsies from V30M patients, asymptomatic carriers, recipients of domino FAP livers as well as transgenic mice for human V30M showed intracellular TTR immunoreactivity in fibroblasts and macrophages that increased with clinical status and with age in transgenic mice. Overall, the present in vitro and in vivo data show that fibroblasts endocytose and degrade TTR aggregates. The function or dysfunction of TTR clearance by fibroblasts may have important implications for the development, progression, and regression of TTR deposition in the ECM. KEYWORDS: amyloidosis; endocytosis; extracellular matrix; familial amyloidotic polyneuropathy; fibroblasts; transthyretin; TTR degradation Transthyretin (TTR)-related amyloidoses are fatal systemic amyloidoses associated with systemic deposition of TTR extracellular amyloid fibrils. TTR-related familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disease related to mutant TTR deposition in various organs and systems, including the peripheral nervous system, eyes, heart, gastrointestinal tract, kidneys, and skin. As of 2012, more than 120 TTR mutations have been discovered, most of which lead to FAP development (http://www.fapwtr.org/ ram_fap.htm); TTR V30M is the most common diseasecausing mutation and occurs in large foci of patients throughout the world. 1 Senile systemic amyloidosis (SSA) is an age-related nonhereditary systemic amyloidosis and mainly affects cardiac functions in elderly people where wild-type (WT) TTR forms amyloid in different tissues. 2 TTR is primarily synthesized by the liver, retina, and choroid plexus of brain, circulates as a soluble tetramer form in blood, cerebrospinal fluid, and aqueous humor, and transports thyroxine and retinol-binding protein. TTR dissociation into monomers is a determining step for partial misfolding, oligomer formation, and fibrillogenesis in tissues. The rate of T...

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