Lopes Douglas M, Llewellyn Sophie K, Bury Sheila E, Wang Jiazheng, Wells Jack A, Gegg Matthew E, Verona Guglielmo, Lythgoe Mark F, Harrison Ian F
Centre for Advanced Biomedical Imaging, Department of Imaging, Division of Medicine, University College London, London, WC1E 6DD, UK.
Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
Brain. 2025 Jul 9. doi: 10.1093/brain/awaf255.
Propagation and aggregation of prion proteins, such as tau and α-synuclein (αSyn), are key pathological features of neurodegenerative diseases. Extracellular clearance pathways, such as the glymphatic system, may 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 polarisation to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated in Parkinson's disease, however the precise mechanisms underlying the pathogenic effect of this dysfunction remain unclear. This includes how impaired glymphatic function influences αSyn propagation dynamics, and the role of propagating αSyn itself on glymphatic function. In this study, we used a mouse model of αSyn propagation to elucidate the impact of αSyn aggregation on glymphatic function, by measuring CSF-ISF 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 αSyn pre-formed fibrils leads to local reduced expression of the AQP4 endfoot complex, but propagation of αSyn pathology induces an enhancement of glymphatic function suggesting compensatory upregulation in response to increasing αSyn aggregate load. To determine the influence of glymphatic dysfunction on αSyn propagation dynamics, we then employed a pharmacological approach to inhibit glymphatic function in this model. Acute glymphatic inhibition significantly reduced brain to CSF clearance of misfolded αSyn, and chronic treatment exacerbated αSyn pathology, cerebral atrophy, and motor behavioural deficits in mice. Together our findings show that αSyn clearance and propagation are modulated by glymphatic function. Moreover, they suggest that AQP4 complex dysregulation may contribute to glymphatic impairment associated with Parkinson's diseases, supporting further mechanistic investigation of this protein complex in the disease.
朊病毒蛋白（如tau蛋白和α-突触核蛋白（αSyn））的传播和聚集是神经退行性疾病的关键病理特征。细胞外清除途径，如类淋巴系统，可能在从大脑中清除这些有毒蛋白质方面发挥关键作用。该系统主要在睡眠期间活跃，依赖水通道蛋白4（AQP4）水通道的表达以及向星形胶质细胞终足的极化，促进间质溶质清除。最近研究表明类淋巴功能障碍与帕金森病有关，然而这种功能障碍的致病作用背后的确切机制仍不清楚。这包括类淋巴功能受损如何影响αSyn的传播动力学，以及传播中的αSyn本身对类淋巴功能的作用。在本研究中，我们使用αSyn传播的小鼠模型，通过测量脑脊液 - 间质液交换，并随时间和跨不同区域评估大脑中的AQP4及相关终足复合蛋白，来阐明αSyn聚集对类淋巴功能的影响。我们的结果表明，直接注射αSyn预形成纤维会导致AQP4终足复合体的局部表达降低，但αSyn病理学传播会诱导类淋巴功能增强，表明对增加的αSyn聚集体负荷有代偿性上调反应。为了确定类淋巴功能障碍对αSyn传播动力学的影响，我们随后采用药理学方法在该模型中抑制类淋巴功能。急性类淋巴抑制显著降低了错误折叠的αSyn从大脑到脑脊液的清除率，慢性治疗加剧了小鼠的αSyn病理学、脑萎缩和运动行为缺陷。我们的研究结果共同表明，αSyn的清除和传播受类淋巴功能调节。此外，它们表明AQP4复合体失调可能导致与帕金森病相关的类淋巴损伤，支持对该疾病中这种蛋白质复合体进行进一步的机制研究。
