Molecular determinants of protein pathogenicity at the single-aggregate level

Abstract

Determining the structure-function relationships of protein aggregates is a fundamental challenge in biology. These aggregates, whether formed in vitro, within cells, or in living organisms, present significant heterogeneity in their molecular features such as size, structure, and composition, making it difficult to determine how their structure influences their functions. Interpreting how these molecular features translate into functional roles is crucial for understanding cellular homeostasis and the pathogenesis of various debilitating diseases like Alzheimers and Parkinsons. In this study, we introduce a bottom-up approach to explore how variations in protein aggregates size, composition, post-translational modifications and point mutations profoundly influence their biological functions. Applying this method to Alzheimers and Parkinsons associated proteins, we uncover the mechanism of novel disease-relevant pathways and demonstrate how subtle alterations in composition and morphology can shift the balance between healthy and pathological states. Our findings establish a broadly applicable framework for investigating protein dysfunctions in various proteinopathies.