Interplay between the glymphatic system and neurotoxic proteins in Parkinson's disease and related disorders: current knowledge and future directions

Abstract

Parkinson's disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins, including α-synuclein, amyloid-β, and tau, in addition to the impaired elimination of these neurotoxic protein. Atypical parkinsonism, which has the same clinical presentation and neuropathology as Parkinson's disease, expands the disease landscape within the continuum of Parkinson's disease and related disorders. The glymphatic system is a waste clearance system in the brain, which is responsible for eliminating the neurotoxic proteins from the interstitial fluid. Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease, as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage. Therefore, impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration. Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson's disease and related disorders; however, many unanswered questions remain. This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson's disease and related disorders. The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins, including loss of polarization of aquaporin-4 in astrocytic endfeet, sleep and circadian rhythms, neuroinflammation, astrogliosis, and gliosis. This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson's disease and related disorders, and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

Figure 1

Schematic representation of the glymphatic system. The glymphatic system is composed of various components, including cerebral spinal fluid (CSF), interstitial fluid (ISF), perivascular spaces, cerebral vessels, glial cells, and astrocyte aquaporin protein-4 (AQP4). Created with BioRender.com.

Figure 2

Non-invasive evaluation of the glymphatic system (unpublished data). (A) Visualization of the perivascular space (PVS) on 7T MRI T2WI images. PVS counting and volume calculation in the basal ganglia to evaluate structural abnormalities of the glymphatic system. (B) Diffusion tensor image along the perivascular space (DTI-ALPS) index for measuring the glymphatic flow. The yellow arrows indicate the PVS in the basal ganglia; the yellow box indicates the medullary vein perpendicular to the lateral ventricle. Unpublished data from the authors' laboratory.

Figure 3

Proteinopathy formation and spread. (A) Formation of Lewy bodies from α-synuclein. The monomeric form of α-synuclein aggregates into oligomers, which further form protofibrils that eventually mature into insoluble fibrils, the main component of Lewy bodies. (B) Formation of amyloid plaques. The amyloid precursor protein is first cleaved by β-secretase and subsequently by γ-secretase to generate amyloid-β (Aβ) peptides, which accumulate and aggregate to form neurotoxic amyloid plaques. (C) Formation of neurofibrillary tangles. The hyperphosphorylated tau proteins assemble and further develop into filamentous neurofibrillary tangles. (D) Cell-to-cell spreading of proteinopathies. Aβ, α-synuclein, and tau seeds can all be transmitted trans-synaptically from one neuron to another, leading to the spread of these protein aggregates throughout the brain. Created with BioRender.com.

Figure 4

Schematic representation of the glymphatic system in pathological states. The enlargement of the perivascular spaces (PVSs) is indicative of structural abnormalities, while a reduction in the diffusion tensor image along the perivascular space (DTI-ALPS) index reflects functional impairment. Created with BioRender.com. AQP4: Aquaporin-4; CSF: cerebral spinal fluid; ISF: interstitial fluid.