The role of the glymphatic system on the severity and distribution of ALPHA-synuclein pathology in ALPHA-synuclein PRE-formed fibril induced rat model of parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease and its prevalence increases in the aging population. Neurotoxicity of α-synuclein (α-syn) pathological accumulations and dopaminergic cell loss play a key role in the pathophysiology of PD. The aim of this study is to investigate the contribution of the glymphatic system to the pathophysiology of PD. The importance of the glymphatic system has recently been better understood as an important pathway in the clearance of macromolecules from the brain. For this purpose, glymphatic system dysfunction was created by ligating lymphatic vessels of deep cervical lymph nodes (dcLN) in a PD rat model induced by injection of α-syn preformed fibrils (PFF) into the striatum. Then, at 6th week, contrast enhanced MRI was performed three times intermittently following intrathecal paramagnetic contrast agent injection by lumbar puncture, and glymphatic system function was evaluated. The transition of contrast agent from subarachnoid space to the brain parenchyma was decreased in the α-syn PFF injected and dcLN ligated group compared to the α-syn PFF group without ligation at 30th and 60th minutes. In the α-syn PFF injected but not dcLN ligated group, decrease in contrast transition was prominent especially in the ventral brainstem at 30th minute post-injection compared to the naive controls. However, this difference disappeared at 60th minute. In the open field and apomorphine-induced locomotor activity tests performed at week 7, there was no significant difference between the groups (p>0.05). In the cylinder test, although there was a trend towards a decrease in the use of contralateral limb in all groups compared to naive controls, no statistical significant difference was detected (p>0.05). Immunohistochemical staining showed α-syn expression and aggregate-like formations in the striatum and substantia nigra, both in the dopaminergic neurons as well as surrounding them. In conclusion, glymphatic system dysfunction is detected in the α-sin PFF model of PD, especially in the brain regions where α-sin pathology was more intense, and dcLN ligation aggravate the dysfunction making it more widespread.