Thiocyanate Reduces Motor Impairment in the hMPO-A53T PD Mouse Model While Reducing MPO-Oxidation of Alpha Synuclein in Enlarged LYVE1/AQP4 Positive Periventricular Glymphatic Vessels

Abstract

Parkinson’s disease (PD) is due to the oxidation of alpha synuclein (αSyn) contributing to motor impairment. We developed a transgenic mouse model of PD that overexpresses the mutated human αSyn gene (A53T) crossed to a mouse expressing the human MPO gene. This model exhibits increased oxidation and chlorination of αSyn leading to greater motor impairment. In the current study, the hMPO-A53T mice were treated with thiocyanate (SCN−) which is a favored substrate of MPO as compared to chlorine. We show that hMPO-A53T mice treated with SCN− have less chlorination in the brain and show an improvement in motor skills compared to the nontreated hMPO-A53T mice. Interestingly, in the hMPO-A53T mice we found a possible link between MPO-related disease and the glymphatic system which clears waste including αSyn from the brain. The untreated hMPO-A53T mice exhibited an increase in the size of periventricular glymphatic vessels expressing the glymphatic marker LYVE1 and aquaporin 4 (AQP4). These vessels also exhibited an increase in MPO and HOCl-modified epitopes in the glymphatic vessels correlating with loss of ependymal cells lining the ventricles. These findings suggest that MPO may significantly promote the impairment of the glymphatic waste removal system thus contributing to neurodegeneration in PD. Moreover, the inhibition of MPO chlorination/oxidation by SCN− may provide a potential therapeutic approach to this disease.

The Implication and Application of Brain Glymphatic System in Multiple Diseases

“…Myeloperoxidase (MPO) increases nitration and aggregation of 𝛼-Syn, and the oxidants it generates damage the glymphatic drainage system. [16,69] Reynolds et al showed that thiocyanate, as a substrate of MPO, could inhibit MPO chlorination/oxidation to decrease the impairment of the glymphatic pathway and suppress the development of PD. [16] Besides, blockage of the meningeal lymphatics may also affect the glymphatic system both in animals and humans.…”

“…[16,69] Reynolds et al showed that thiocyanate, as a substrate of MPO, could inhibit MPO chlorination/oxidation to decrease the impairment of the glymphatic pathway and suppress the development of PD. [16] Besides, blockage of the meningeal lymphatics may also affect the glymphatic system both in animals and humans. [50,67] Table 1.…”

“…showed that thiocyanate, as a substrate of MPO, could inhibit MPO chlorination/oxidation to decrease the impairment of the glymphatic pathway and suppress the development of PD. [ 16 ] Besides, blockage of the meningeal lymphatics may also affect the glymphatic system both in animals and humans. [ 50,67 ] In A53T mice, blockade of meningeal lymphatic drainage induced reactive astrocytes, impaired AQP‐4 polarization, reduced CSF flow, and increased aggregation of α‐Syn.…”

“…Considering the imperative role of the glymphatic system in the clearance of wastes, its dysregulation contributes to the massive deposition of toxic metabolic wastes in the brain. [14][15][16] The main pathological features of glymphatic system dysfunction are CSF generation and flow reduction, glymphatic space shrinkage, decreased levels of AQP-4 polarization, hyperproliferation of reactive astrocytes, etc. [17][18][19] These changes can impact the brain's ability to effectively clear toxins, potentially contributing to the progression of diseases.…”