The role of transthyretin in cell biology: impact on human pathophysiology

Abstract

Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol throughout the body and brain. TTR is prone to aggregation, as both wild-type and mutated forms of the protein can lead to the accumulation of amyloid deposits, resulting in a disease called TTR amyloidosis. Recently, novel activities for TTR in cell biology have emerged, ranging from neuronal health preservation in both central and peripheral nervous systems, to cellular fate determination, regulation of proliferation and metabolism. Here, we review the novel literature regarding TTR new cellular effects. We pinpoint TTR as major player on brain health and nerve biology, activities that might impact on nervous systems pathologies, and assign a new link between TTR and angiogenesis and cancer. We also explore the molecular mechanisms underlying TTR activities at the cellular level, and suggest that these might go beyond its most acknowledged carrier functions and include interaction with receptors and activation of intracellular signaling pathways.

Keywords: Cell metabolism; Neuronal health; Neuroprotection; Proliferation; Transthyretin.

Fig.1

Structure of human transthyretin (TTR) tetramer in complex with two thyroxine (T₄) molecules (stick models) bound in the central hydrophobic channel (A), and with two molecules of retinol-binding protein (RBP) bound to the external surface (green and yellow) (B). Structural data obtained from pdb files (2ROX and 1QAB)

Fig. 2

Transthyretin (TTR) role on neuronal cell biology. A TTR neuroprotective role. Extracellular TTR controls neuronal health, outgrowth and function via receptors (megalin, GABA_A-R and IGF1-R). B Extracellular TTR aggregates (agTTR) cause neurotoxicity via the receptor RAGE. Other unknown receptors might be involved in the pathways impacted by extracellular TTR

Fig. 3

Transthyretin (TTR) novel roles in: A cell fate, with TTR absence inducing oligodendrogenesis; B stimulation if cell proliferation via AKT; C immune regulation, by controlling myeloid cell differentiation; and D cell metabolism, via AKT, in difference cell types

Fig. 4

Transthyretin (TTR) induces neuroprotection, immune modulation, and impacts in cellular proliferation and cell metabolism. How TTR impacts the cells is still unknown, but at least four pathways have been proposed. (1) TTR as a carrier of hormones, (2) TTR as a proteolytic enzyme, (3) TTR binding to receptors and inducing signal transduction events, and (4) direct effect of intracellular TTR on cellular pathways