The Glymphatic System–Neurodegeneration Axis: Its Role in Parkinson’s Disease and Therapeutic Potential

The glymphatic system has been proposed as a brain-wide perivascular clearance pathway involved in the exchange of cerebrospinal fluid and interstitial fluid. As a dynamic clearance network, it plays key roles in regulating fluid exchange between the cerebrospinal and interstitial compartments, facilitating the removal of metabolic waste and misfolded proteins, and supporting cerebral microcirculation. Proper functioning of the glymphatic system is regarded as contributing to the maintenance of brain health, while its dysfunction has been associated with protein aggregation, neuroinflammation, and neurodegenerative processes. In particular, the perivascular localization and polarization of aquaporin-4 (AQP4) channels are considered critical determinants of glymphatic flow. Although the glymphatic system has emerged as an important component in maintaining brain homeostasis, the mechanisms regulating its function and its relationship with neurological disorders have not yet been fully elucidated. The clearance of α-synuclein via glymphatic pathways and its association with AQP4 represent a promising area of investigation in Parkinson’s disease (PD). A more comprehensive understanding of the glymphatic system may contribute to the development of therapeutic strategies not only for PD, but also for other central nervous system disorders. This review discusses the structure of the glymphatic system, the factors affecting its function, its relationship with central nervous system diseases, and particularly its role in PD, while highlighting the relevance of this system in the context of therapeutic approaches.