PA02_01 - Structural pathways of α-synuclein misfolding from condensates to toxic fibrils

PA02_01

Structural pathways of α-synuclein misfolding from condensates to toxic fibrils

A. De Simone^1,*

¹Pharmacy, University of Naples Federico II, Naples, Italy

 

Abstract: The misfolding and aggregation of α-synuclein (αS) into insoluble amyloid fibrils is associated with a number of neurodegenerative conditions collectively known as synucleinopathies, including Parkinson’s Disease (PD). Despite recent advances such as the determination of atomic-resolution structures of ex vivo fibrils from PD patients, major challenges persist in elucidating the molecular mechanisms underlying αS misfolding. A key limitation stems from the inherent difficulties in isolating and characterising intermediate species along the amyloid pathway, as these are typically short-lived, heterogeneous and in rapid equilibrium with higher-order assemblies. We have established a research programme combining structural biology and cellular biophysics to enable the characterisation of transient species involved in pathological αS aggregation, ranging from monomers [1, 2] to oligomers [3] and protofibrils that arise from liquid-liquid phase separation [4]. Through these investigations, we seek to elucidate the mechanisms by which misfolded αS conformations contribute to neurotoxicity in vitro and in vivo.

 

References

1. Fusco et al, Nat Commun, 2016. 7:12563.

2. Gallo et al, JACS Au, 2024. 4:2372-2380.

3. Fusco et al, Science, 2017. 358:1440-1443.

4. Chen et al, J Am Chem Soc, 2024. 146:10537-10549.

Disclosure of Interest: None declared