{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTransthyretin (TTR) is a highly conserved homotetrameric protein synthesized mainly in the liver and the choroid plexus that plays a central role in the systemic transport of thyroxine and retinol (via retinol‐binding protein). In addition to its canonical function as a carrier, TTR exerts a range of ancillary activities that impact neurobiology and metabolism. For example, it has been implicated in neuroregenerative processes, supports axonal growth, and facilitates the clearance of amyloid‐β peptide at the blood–brain barrier, suggesting a neuroprotective and neuromodulatory role. TTR also exhibits a mild proteolytic activity against substrates such as apolipoprotein A‑I. Moreover, altered levels of TTR have been explored as surrogate indicators of nutritional status and systemic acute phase responses in various disorders including depression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUnder pathological conditions, however, TTR can dissociate from its native tetramer and misfold, leading to the formation of amyloid fibrils that underlie a spectrum of systemic and familial amyloid diseases. Structural and biochemical investigations have identified critical regions of the TTR molecule—such as specific β‐strands, loop segments, and transient “β‐slip” intermediates—that dictate its propensity for misassembly. Mutations (for example, V30M and T119M) and post‐translational modifications (including oxidative changes) modulate TTR’s kinetic stability and favor the generation of small cytotoxic oligomers that can precede fibril formation. Advanced approaches, including high‐pressure studies, mass spectrometry and NMR spectroscopy, have provided molecular insights into the aggregation process and enabled the design of peptide inhibitors that stabilize the native structure."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, the TTR amyloidoses manifest as heterogeneous disorders that can involve the peripheral nervous system and the heart, with pathogenic variants (such as V30M and V122I) showing variable penetrance and distinct phenotypic profiles across populations. Early diagnostic approaches now integrate genetic testing and biomarker assessment, while therapeutic strategies increasingly focus on stabilizing the native tetramer with small-molecule ligands (for instance, tafamidis) to impede dissociation and subsequent fibril formation. Novel analytical techniques such as subunit exchange assays further enable the quantitative evaluation of TTR stabilization in patient plasma. These advances not only deepen our understanding of the molecular pathology of TTR aggregation but also pave the way for tailored interventions in familial and senile amyloid cardiomyopathies and neuropathies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "A Myron Johnson, Giampaolo Merlini, Joanna Sheldon, et al. 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