The Glymphatic System in α-Synucleinopathies.

α-Synucleinopathies-including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)-are neurodegenerative disorders characterized by the pathological accumulation of misfolded α-synuclein. While current treatments remain largely symptomatic, emerging evidence suggests that impaired clearance of toxic proteins may underlie disease progression. The glymphatic system, a brain-wide network facilitating cerebrospinal fluid (CSF)-mediated waste removal through perivascular pathways and astrocytic aquaporin-4 (AQP4) channels, has gained attention as a key regulator of protein homeostasis in the central nervous system. This review synthesizes recent neuroimaging, pathological, and experimental data linking glymphatic dysfunction to α-synucleinopathies. Advanced MRI methods-including diffusion tensor imaging analysis along perivascular spaces (DTI-ALPS) and functional blood oxygen-level dependent-CSF coupling-reveal impaired glymphatic flow in PD, DLB, and MSA, with correlations to cognitive and motor decline. Animal and postmortem studies demonstrate that disruption of AQP4 polarization exacerbates α-synuclein accumulation and neurodegeneration. Furthermore, reduced glymphatic clearance may promote neuroinflammation and disease spread. These findings highlight the glymphatic system as a potentially modifiable contributor to α-synucleinopathy pathogenesis. Therapeutic strategies to enhance glymphatic clearance-including sleep optimization, pharmacologic modulation of AQP4, and novel device-based approaches-are under active investigation. Targeting the brain's waste-clearance infrastructure may offer a new disease-modifying avenue in the treatment of α-synucleinopathies.