Rising Stars: Molecular Mechanisms and Chemical Interventions of α-Synuclein Amyloid Aggregation in Parkinson's Disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by progressive neuronal loss and pathological aggregation of α-synuclein (α-syn) into amyloid fibrils, which propagate between cells and drive disease progression. Over the past decade, our laboratory has implemented an integrated strategy-combining high-resolution structural biology, molecular biophysics, biochemical and cellular analyses, chemical biology approaches, and in vivo disease models-to elucidate the molecular basis of α-syn pathology. We first determined atomic-resolution structures of full-length α-syn fibrils, revealing diverse polymorphs shaped by familial mutations and post-translational modifications, and linking conformational heterogeneity to phenotypic and pathological diversity. We further elucidated the structural basis underlying the interaction between amyloid fibril and chemical ligands, enabling the rational development of imaging probes and therapeutic modulators. In parallel, we found that the conserved acidic C-terminal region of α-syn fibrils acts as a central interface for driving pathogenic engagement with multiple receptors for neural propagation and inflammation induction, while also binding the autophagy adaptor LC3B to disrupt p62-mediated selective autophagy. Targeting this interface with small molecule inhibitors alleviates α-syn-induced toxicity in cellular models. Together, these findings provide an integrated molecular roadmap for understanding α-syn pathology and advancing precision diagnostics and targeted interventions in PD and related synucleinopathies.