Molecular understanding of liquid–liquid phase separation of α-synuclein for the development of novel Parkinson’s disease therapies

α-Synuclein (α-syn) exists abundantly at presynaptic terminals and plays a pivotal role in vesicle trafficking and neurotransmitter release thereafter. α-Syn exhibits structural plasticity and adopts diverse conformations such as α-helices and β-strands in response to adjacent microenvironments. These structural features facilitate the formation of aberrant α-syn condensates under specific circumstances. Aggregates and amyloid fibrils of α-syn have been observed in the brain tissue of patients with Parkinson’s disease (PD) and other synucleinopathies. Τhe nucleation of α-syn as a precursor to aggregation and amyloid formation is associated with liquid–liquid phase separation (LLPS), which forms droplets in solution. Thus, elucidating the detailed molecular formation of α-syn LLPS is necessary to understand the aberrant polymerization of α-syn, such as the formation of amyloid fibrils. In this review, we describe the formation mechanism of α-syn LLPS. In addition, we discuss several molecular strategies for targeting α-syn LLPS to block the formation of α-syn aggregates or amyloid fibrils. This review provides biophysical insights for the development of novel therapies for PD.