Unfolding Sequence-Specific Enigma in Monomeric α-Synuclein: Implications for Parkinson's Disease

Parkinson's disease (PD) is a debilitating neurological disorder characterized by the buildup of abnormal protein clumps, primarily composed of a protein called Alpha-Synuclein (α-Syn). Under physiological conditions, α-Syn exists as a dynamic, intrinsically disordered protein that resists aggregation through transient intramolecular interactions. However, under pathological conditions, this protein can misfold and stack into rigid, fibrous structures known as amyloid fibrils. These fibrillar deposits accumulate within neurons and are central to PD pathogenesis. This review focuses on understanding what keeps monomeric α-Syn in its innocuous form and what causes it to shift into a disease-associated state. In particular, we explore the role of subtle, often-overlooked intramolecular forces, like cation-π, π-π, and CH-π interactions, that may help stabilize the protein and prevent aggregation. We also examine how genetic mutations linked to familial forms of PD influence these internal interactions and drive the formation of partially folded intermediate forms that can trigger fibril growth. Some familial mutations accelerate α-Syn aggregation, while others slow it down, but the reasons behind these different outcomes are not fully understood. By analyzing how these mutations alter the protein's early structure and behavior, this review aims to shed light on the first steps of α-Syn misfolding. A deeper understanding of these mechanisms could support the development of new therapies designed to stabilize the soluble form of monomeric α-Syn and slow or prevent disease progression.