From biophysical chemistry to cell biology: Deciphering the role of lipids in the toxicity and spreading of protein aggregation

The LIPAGG project seeks to unravel the structural complexities of amyloid protein-lipid aggregates and investigate their role in pathological aggregation, cellular toxicity, and intercellular spread. Focusing on key human amyloid proteins—amylin (IAPP), amyloid beta (Aβ), and α-synuclein (αS)—linked to type 2 diabetes (T2D), Alzheimer's disease (AD), and Parkinson’s disease (PD), respectively, the project builds on recent discoveries made by the consortium. These findings highlight the critical role of free lipids in membrane damage through the formation of stable lipid-amyloidogenic protein complexes, leading to the lipid-chaperone hypothesis.The project will explore unresolved mechanisms linking amyloid aggregation to cellular damage, focusing on three key aspects: 1) the toxicity of prefibrillar amyloid oligomers, 2) the interaction of amyloid proteins with lipid membranes, and 3) the pathological spread of amyloid aggregates in the brain. Guided by the lipid-chaperone hypothesis, the consortium will train fifteen Doctoral Candidates (DCs), emphasizing the pivotal role of lipids in amyloid-related diseases. The training program will include cutting-edge methods in biophysics, peptide chemistry, molecular and structural biology, and cell biology.The scientific objectives of LIPAGG include characterizing amyloid-lipid complexes, understanding their impact on aggregation and membrane integrity, assessing their effects on cellular viability and intercellular spread, and developing chemical tools to block the formation of these complexes, offering potential therapeutic strategies. The results will have significant societal impact, enhancing our understanding of AD, PD, and T2D, including potential improvements in diagnostic and therapeutic approaches. With support of a consortium of 23 partners from 8 countries, DCs will have access to state-of-the-art instrumentation, including 1.2 GHz NMR spectrometers, single-particle cryo-EM facilities, and supercomputers.