Probing the Druggable Space of Transthyretin

• Applicant: Dr. Jan-Hannes Schäfer
• Subject Area: Structural Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 556478029

Neurodegenerative diseases (NDDs) impair cognitive and motor functions, resulting from the progressive loss of neurons. A key pathological hallmark of NDDs is the formation of cytotoxic protein aggregates, classifying them as proteinopathies. Proteins and peptides associated with proteinopathies undergo conformational changes that promote their integration into proteolysis-resistant “amyloids”. Transthyretin amyloidosis (ATTR) is the third most common NDD after Alzheimer’s and Parkinson’s, originating from thyroxine-carrier transthyretin (TTR). Despite five decades of structural studies on TTR, the molecular determinants underlying ATTR pathology remain poorly understood. The limited structural knowledge of ligand binding allostery and amyloidogenic TTR unfolding intermediates contribute to this gap, ultimately hindering the development of new anti-ATTR drugs. In this proposal, I will use single-particle cryo-electron microscopy (cryo-EM) of recombinant and patient-derived TTR-variants to investigate the druggable space of Transthyretin. This work aims to identify the structural basis for TTR tetramer destabilization, pinpoint determinants of TTR aggregation along a series of oligomerization intermediates, and find structural evidence for the proposed neuroprotective effect of TTR against Aβ fibrillogenesis. The elucidation of high-resolution structures across the conformational landscape of tetrameric to filamentous non-amylogenic TTR will be an important step in understanding the principles of progressive proteinopathies. Additionally, this proposal may clarify the mechanism of TTR-driven neuroprotection from Aβ fibrillogenesis. Overall, this work will establish the methodological and mechanistic principles for future structure-function & proteotoxicity studies on TTR, and also reveal new avenues for therapeutic intervention in general.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Gabriel Lander, Ph.D.