Targeting the glymphatic system to promote α-synuclein clearance:a novel therapeutic strategy for Parkinson's disease
Xiaoyue Lian1
Zhenghao Liu1
Zuobin Gan1
Qingshan Yan1
Luyao Tong1
Linan Qiu2
Yuntao Liu1
Jiang-fan Chen2
Zhihui Li2
1.Molecular Neuropharmacology Laboratory and Eye-Brain Research Center,State Key Laboratory of Ophthalmology,Optometry and Vision Science,School of Ophthalmology &Optometry and Eye Hospital,Wenzhou Medical University,Wenzhou,Zhejiang Province,China2.Molecular Neuropharmacology Laboratory and Eye-Brain Research Center,State Key Laboratory of Ophthalmology,Optometry and Vision Science,School of Ophthalmology &Optometry and Eye Hospital,Wenzhou Medical University,Wenzhou,Zhejiang Province,China;Oujiang Laboratory(Zhejiang Laboratory for Regenerative Medicine,Vision and Brain Health),School of Ophthalmology & Optometry and Eye Hospital,Wenzhou Medical University,Wenzhou,Zhejiang Province,China
摘要：The excessive buildup of neurotoxic α-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease,highlighting the urgent need for innovative therapeutic strategies to promote α-synuclein clearance,particularly given the current lack of disease-modifying treatments.The glymphatic system,a recently identified perivascular fluid transport network,is crucial for clearing neurotoxic proteins.This review aims to synthesize current knowledge on the role of the glymphatic system inα-synuclein clearance and its implications for the pathology of Parkinson's disease while emphasizing potential therapeutic strategies and areas for future research.The review begins with an overview of the glymphatic system and details its anatomical structure and physiological functions that facilitate cerebrospinal fluid circulation and waste clearance.It summarizes emerging evidence from neuroimaging and experimental studies that highlight the close correlation between the glymphatic system and clinical symptom severity in patients with Parkinson's disease,as well as the effect of glymphatic dysfunction on α-synuclein accumulation in Parkinson's disease models.Subsequently,the review summarizes the mechanisms of glymphatic system impairment in Parkinson's disease,including sleep disturbances,aquaporin-4 impairment,and mitochondrial dysfunction,all of which diminish glymphatic system efficiency.This creates a vicious cycle that exacerbates α-synuclein accumulation and worsens Parkinson's disease.The therapeutic perspectives section outlines strategies for enhancing glymphatic activity,such as improving sleep quality and pharmacologically targeting aquaporin-4 or its subcellular localization.Promising interventions include deep brain stimulation,melatonin supplementation,y-aminobutyric acid modulation,and non-invasive methods(such as exercise and bright-light therapy),multisensory y stimulation,and ultrasound therapy.Moreover,identifying neuroimaging biomarkers to assess glymphatic flow as an indicator of α-synuclein burden could refine Parkinson's disease diagnosis and track disease progression.In conclusion,the review highlights the critical role of the glymphatic system in α-synuclein clearance and its potential as a therapeutic target in Parkinson's disease.It advocates for further research to elucidate the specific mechanisms by which the glymphatic system clears misfolded α-synuclein and the development of imaging biomarkers to monitor glymphatic activity in patients with Parkinson's disease.Findings from this review suggest that enhancing glymphatic clearance is a promising strategy for reducing α-synuclein deposits and mitigating the progression of Parkinson's disease.
机标关键词：parkinsonstrategysystemnovelclearancediseaseglymphaticpromote
论文发表日期：2026-01-30
在线出版日期：2025-12-11（本平台首次上网日期，不代表文献的发表时间）
页数：15( 233-247 )
英文信息