Abstract
Purpose :
α-Synuclein (α-Syn) is implicated in Parkinson’s disease (PD), a neuro-motor disorder with prominent ocular symptoms. Here, we explored whether α-Syn plays a functional role in the anterior segment of the eye, and whether its dysfunction due to aggregation contributes to ocular pathology.
Methods :
Primary human trabecular meshwork (TM) cells, cadaveric human and bovine TM tissue and aqueous humor (AH), and human AH collected during cataract surgery were used for this study. Silencing of α-Syn and overexpression of TGFβ2 in TM cells and tissue was achieved by conventional techniques. Expression of fibronectin (FN), α-smooth muscle actin (α-SMA), and ROCK-1 was determined by Western blotting (WB). Binding, uptake, and response of TM cells to extracellular α-Syn was determined by immunostaining and WB.
Results :
α-Syn was expressed in the ciliary body and TM, and monomeric and oligomeric α-Syn was present in the AH. Silencing of α-Syn in TM cells downregulated FN, α-SMA, and ROCK-1 expression in the absence and presence of active TGFβ2. Extracellular monomeric and oligomeric α-Syn was internalized by β1-integrin, and upregulated FN, α-SMA, and ROCK-1 in TM cells and TM tissue. Active TGFβ2 was also increased.
Conclusions :
Intracellular α-Syn altered the expression of extracellular matrix (ECM) proteins in TM cells through ROCK-1 independently and downstream of TGFβ2, the principal trigger for dysregulation of ECM in primary open angle glaucoma (POAG). Extracellular α-Syn was endocytosed by TM cells through β1-integrin, and likewise, upregulated ECM proteins. These observations have significant implications for POAG, and warrant exploration of the underlying biochemical pathways.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.