Transthyretin (TTR), formerly known as prealbumin, is a tetrameric transport protein primarily synthesized in the liver and the choroid plexus. It is best known for its role in transporting thyroxine (T4) and retinol (via retinol-binding protein). However, TTR has garnered significant attention in neurodegeneration research due to its propensity to misfold and form amyloid deposits in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA).
TTR exists as a homotetramer, composed of four identical subunits arranged in a dimer-of-dimers configuration. Each subunit contains: [1]
Over 100 TTR mutations are known, with the most neurodegenerative-relevant include: [2]
TTR binds and transports T4 (thyroxine) in cerebrospinal fluid (CSF) and plasma. The thyroid hormone binding site is located at the tetramer interface. [3]
TTR forms a complex with retinol-binding protein (RBP) to transport vitamin A (retinol). This interaction stabilizes both proteins and prevents renal filtration of RBP. [4]
| Drug | Mechanism | Status | [5]
|------|-----------|--------|
| Tafamidis (Vyndaqel) | TTR stabilizer | Approved (FAP) |
| Diflunisal | NSAID/TTR stabilizer | Phase 3 |
| Acoramidis | TTR stabilizer | Phase 3 |
| AG10 | TTR stabilizer | Phase 2 |
| Approach | Target | Status |
|---|---|---|
| Patisiran (Onpattro) | siRNA to TTR mRNA | Approved (FAP) |
| Vutrisiran (Amvuttra) | siRNA to TTR mRNA | Approved (FAP) |
| Inotersen (Tegsedi) | Antisense oligonucleotide | Approved (FAP) |
| Partner | Interaction Type | Relevance |
|---|---|---|
| Retinol-binding Protein | Complex formation | Vitamin A transport |
| Thyroxine (T4) | Ligand binding | Hormone transport |
| Hsp70 | Chaperone binding | Protein folding |
| Hsp90 | Chaperone binding | Protein folding |
| IDE | Protease degradation | Aβ degradation |
| Neprilysin | Protease | Amyloid clearance |
Coelho et al. [Tafamidis for V30M ATTR polyneuropathy (2023)](https://doi.org/10.1016/S1474-4422(23). 2023. ↩︎
Adams et al. Patisiran for hereditary ATTR amyloidosis (2023). 2023. ↩︎
Sekijima et al. Pathogenesis of TTR amyloidosis (2022). 2022. ↩︎
Sant'Anna et al. TTR tetramer dynamics and dissociation (2021). 2021. ↩︎
Buxbaum & Tagoe, The pathogenesis of transthyretin amyloidosis (2020). 2020. ↩︎