Elucidating Pathological Mechanisms and Developing Biomarkers of Parkinson's Disease

ABSTRACT Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor and non‐motor symptoms. A combination of genetic predispositions and environmental factors is thought to contribute to the development of PD. We highlight molecular, cellular, and systemic mechanisms underlying PD, particularly α‐synuclein propagation, LRRK2 function, lipid metabolism, and metabolomic alterations. Studies on α‐synuclein have highlighted its prion‐like behavior, characterized by the propagation of pathological aggregates across neural circuits, significantly contributing to disease progression. Dysregulation of lipid metabolism, driven by mutations in genes such as PSAP and PLA2G6 , has been shown to accelerate α‐synuclein aggregation, providing critical insights into the disease's biochemical pathways. LRRK2 , the second most prevalent causative gene of autosomal dominant familial PD, has been implicated in tau phosphorylation and vesicle trafficking. Moreover, metabolomic analyses of blood samples from PD and PARK2 patients have identified alterations in lipid and amino acid metabolism, revealing potential systemic disease mechanisms and biomarkers for diagnosis and prognosis. These findings collectively inform the development of advanced diagnostic tools and innovative therapeutic strategies. By integrating molecular‐level studies with systemic approaches, the goal of our research is to deepen our understanding of PD pathology, bridge the gap between central and peripheral disease mechanisms, and accelerate the development of disease‐modifying therapies that will resolve the unmet medical needs for both motor and non‐motor symptoms in PD. This review summarized an overview of my research on “Elucidation of the Pathology of Parkinson's Disease and the Development of Disease Biomarkers,” which was awarded the 2024 Japan Neurological Society Prize.