Toll like receptor 2 mediated alpha synuclein pathology in Parkinsons disease

Abstract

α-Synuclein (αSyn) plays a critical role in the pathogenesis of Parkinson's disease (PD). Initially, it was thought to exist exclusively within cells. However, evidence suggests its presence in cerebrospinal fluid, plasma, and the culture media of neuronal cells. Recent findings indicate that suppressing the autophagy-lysosome pathway (ALP) promotes the release of αSyn, with a fraction of it being secreted through extracellular vesicles (EVs). The extracellular αSyn has been observed to activate microglia, propagate to neurons and astrocytes, inducing inflammatory responses and causing cell death in neurons. Additionally, our previous research demonstrated that toll-like receptor 2 (TLR2), a receptor involved in innate immunity, exhibits a substantial increase in the brains of individuals with PD. Moreover, the activation of TLR2 in neural cells inhibits ALP and increases the levels of endogenous αSyn. This led us to hypothesize that stimulating neuronal TLR2 would also enhance the release of αSyn into the extracellular space. To investigate this, we treated SH-SY5Y cells overexpressing αSyn with a TLR2 agonist called Pam3CSK4. Our results revealed an increase in both intracellular and extracellular αSyn levels following the treatment. Furthermore, TLR2 activation also increased the secretion of particles containing markers of microvesicles and exosomes, with higher levels of αSyn detected in the EVs released by Pam3CSK4-treated cells. Moreover, when exposing wild-type SH-SY5Y cells to the conditioned media, we observed the transmission of the released αSyn to the recipient cells. Additionally, the released αSyn can function as an agonist, activating TLR2 in the recipient neuron. In summary, our findings suggest that activating neuronal TLR2 enhances the release of αSyn, which can be internalized by adjacent wild-type SH-SY5Y cells, potentially contributing to the progression of PD.