Propagation and aggregation of prion proteins, such as tau and α-synuclein (α-syn), are key pathological features of neurodegenerative diseases. Extracellular clearance pathways, such as the glymphatic system, might play a crucial role in the removal of these toxic proteins from the brain. Primarily active during sleep, this system relies on aquaporin-4 (AQP4) water channel expression and polarization to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated in Parkinson's disease, but the precise mechanisms underlying the pathogenic effect of this dysfunction remain unclear. This includes how impaired glymphatic function influences α-syn propagation dynamics, in addition to the role of propagating α-syn itself on glymphatic function. In this study, we used a mouse model of α-syn propagation to elucidate the impact of α-syn aggregation on glymphatic function by measuring CSF-interstitial fluid exchange and assessing AQP4 and associated endfoot complex proteins in the brain over time and across different regions. Our results show that direct injection of α-syn preformed fibrils leads to local reduced expression of the AQP4 endfoot complex, but propagation of α-syn pathology induces an enhancement of glymphatic function, suggesting compensatory upregulation in response to increasing α-syn aggregate load. To determine the influence of glymphatic dysfunction on α-syn propagation dynamics, we then took a pharmacological approach to inhibit glymphatic function in this model. Acute glymphatic inhibition significantly reduced brain-to-CSF clearance of misfolded α-syn, and chronic treatment exacerbated α-syn pathology, cerebral atrophy and motor behavioural deficits in mice. Together, our findings show that α-syn clearance and propagation are modulated by glymphatic function. Moreover, they suggest that AQP4 complex dysregulation might contribute to glymphatic impairment associated with Parkinson's disease, supporting further mechanistic investigation of this protein complex in the disease.
