Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (on line): 1-18.

   

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 Qiu1, 2, Yuntao Liu1 , Jiang-fan Chen1, 2, *, Zhihui Li1, 2, *   

  1. 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, China; 2 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
  • Online:2025-01-01 Published:2024-12-12
  • Contact: Jiang-fan Chen, MD, PhD, chenjf555@gmail.com; Zhihui Li, PhD, smart_dream@wmu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 81971031 (to ZL); the National Key Research and Development Program of China, No. 2022YFE0210100 (to JFC); the National Natural Science Foundation of China (Original Exploration Project), No. 82151308 (to JFC); the National Natural Science Foundation of China (Research Fund for International Senior Scientists), No. 82150710558 (to JFC); Science & Technology Initiative STI2030-Major Projects, No. 2021ZD0203400 (to JFC); Key Research and Development Program of Zhejiang Province, No. 2023C03079 (to JFC); Scientific Research Starting Foundation of Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), No. OJQDSP2022007 (to JFC); Project of State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou Medical University, No. J01-20190101 (to JFC); Scientific Research Starting Foundation of Wenzhou Medical University, No. QTJ12003 (to JFC); Department of Science and Technology of Zhejiang Province, No. 2023ZY1011 (to JFC).

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Abstract: 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 in α-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, γ-aminobutyric acid modulation, and non-invasive methods (such as exercise and bright-light therapy), multisensory γ 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.

Key words: aquaporin-4, astrocytes, cerebrospinal fluid, glymphatic system, interstitial fluid, neurotoxic protein clearance, Parkinson’s disease, perivascular spaces, sleep disturbance, α-synuclein