α-Synuclein aggregation landscape from phase separation to neurotoxic intermediates

The aberrant aggregation of α-synuclein (αS) into insoluble amyloid fibrils is a hallmark of Parkinson's disease. Despite recent advances in characterising the properties of mature αS fibrils, the transient and heterogeneous intermediates that underlie cellular toxicity remain largely elusive. Here, we review the mechanistic principles of αS aggregation, focussing on liquid-liquid phase separation (LLPS) as a critical intermediate step. We discuss how the structural evolution of αS within the condensed phase governs the subsequent patterns of cellular dysfunction and pathological propagation. This framework supports an emerging state-centric paradigm in therapeutic discovery, where the physical properties of αS condensates are modulated to mitigate the deleterious effects of its misfolding, offering a new sophisticated alternative to classical inhibition strategies.