**2. Transthyretin (TTR)**

TTR is a 127 amino acid protein, is encoded by 7 kb of DNA spanning exons 1–4 of a single gene on chromosome 18 [4]. TTR is a carrier molecule of thyroxine and vitamin A. Serum TTR is synthesized and excreted by the liver as a tetrameric structure. Other sources of local TTR synthesis include epithelial cells of the choroid plexus and the retinal pigment epithelium. TTR is however dispensable for thyroid hormone homeostasis; TTR knockout mice are euthyroid and have a normal phenotype [5, 6]. The presence of point mutations in TTR results in destabilization of the tetramere, and dissociation into amyloidogenic monomers, which misfold and self-aggregate into insoluble amyloid fibrils (**Figure 1**). Two distinct types of amyloid fibrils have been described in TTR amyloid deposits: type A, consists of C-terminal TTR fragments and full-length TTR, and type B, which only consists of full-length TTR [7]. Type A fibrils often target the heart and type B fibrils occur predominantly with neurological symptoms [8]. Every organ of an individual patient contains the same (either type A or type B) fibrils, and the composition is unchanged over time. The presence of C-terminal TTR fragments has an impact on the affinity for various tracers used for intensity of tissue Congo red staining and of noninvasive imaging of amyloid depositions using 99 m-technetium-diphosphono-propanodicarboxylic acid scintigraphy [7].

#### **Figure 1.**

*Amyloid formation by TTR requires rate-limiting tetramer dissociation to a pair of folded dimers, which then quickly dissociate into folded monomers. Partial unfolding of the monomers yields the aggregation-prone amyloidogenic intermediate. The amyloidogenic intermediate can misassemble to form a variety of aggregate morphologies, including spherical oligomers, amorphous aggregates, and fibrils. Tafamidis binding to the TTR tetramer (upper left, see text below) dramatically slows dissociation, thereby efficiently inhibiting aggregation [from [63], with permission].*
