Interaction Between the Glymphatic System and α-Synuclein in Parkinson’s Disease

• Published in: Molecular neurobiology 2023-04, Vol.60 (4), p.2209-2222
• Main Authors: Zhang, Yu, Zhang, Cui, He, Xu-Zhong, Li, Zhen-Hua, Meng, Jing-Cai, Mao, Rui-Ting, Li, Xin, Xue, Rong, Gui, Qian, Zhang, Guo-Xing, Wang, Lin-Hui
• Format: Article
• Language: English
• Subjects: Acetazolamide; alpha-Synuclein - metabolism; Alzheimer Disease; Alzheimer's disease; Animals; Aquaporin 4; Aquaporins; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; Cell Biology; Cerebrospinal fluid; CRISPR; Dopamine receptors; Gene deletion; Glymphatic System - metabolism; Humans; Mice; Movement disorders; Mutation; Neurobiology; Neurodegenerative diseases; Neurology; Neurosciences; Parkinson Disease - genetics; Parkinson's disease; Pathology; Synuclein; Therapeutic targets; Transgenic animals; β-Amyloid
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-023-03212-2

The glymphatic system contributes to the clearance of amyloid-β from the brain and is disrupted in Alzheimer’s disease. However, whether the system is involved in the removal of α-synuclein (α-syn) and whether it is suppressed in Parkinson’s disease (PD) remain largely unknown. In mice receiving the intranigral injection of recombinant human α-syn, we found that the glymphatic suppression via aquaporin-4 (AQP4) gene deletion or acetazolamide treatment reduced the clearance of injected α-syn from the brain. In mice overexpressing the human A53T-α-syn, we revealed that AQP4 deficiency accelerated the accumulation of α-syn, facilitated the loss of dopaminergic neurons, and accelerated PD-like symptoms. We also found that the overexpression of A53T-α-syn reduced the expression/polarization of AQP4 and suppressed the glymphatic activity of mice. The study demonstrates a close interaction between the AQP4-mediated glymphatic system and parenchymal α-syn, indicating that restoring the glymphatic activity is a potential therapeutic target to delay PD progression.