α-Synuclein modulates fibronectin expression in the trabecular meshwork independent of TGFβ2

alpha-Synuclein (alpha-Syn) is implicated in Parkinson's disease (PD), a neuromotor disorder with prominent visual symptoms. The underlying cause of motor dysfunction has been studied extensively, and is attributed to the death of dopaminergic neurons mediated in part by intracellular aggregation of alpha-Syn. The cause of visual symptoms, however, is less clear. Neuroretinal degeneration due to the presence of aggregated alpha-Syn has been reported, but the evidence is controversial. Other symptoms including those arising from primary open angle glaucoma (POAG) are believed to be the side-effects of medications prescribed for PD. Here, we explored the alternative hypothesis that dysfunction of alpha-Syn in the anterior eye alters the interaction between the actin cytoskeleton of trabecular meshwork (TM) cells with the extracellular matrix (ECM), impairing their ability to respond to physiological changes in intraocular pressure (IOP). A similar dysfunction in neurons is responsible for impaired neuritogenesis, a characteristic feature of PD. Using cadaveric human and bovine TM tissue and primary human TM cells as models, we report two main observations: 1) alpha-Syn is expressed in human and bovine TM cells, and significant amounts of monomeric and oligomeric alpha-Syn are present in the AH, and 2) primary human TM cells and human and bovine TM tissue endocytose extracellular recombinant monomeric and oligomeric alpha-Syn via the prion protein (PrPC), and upregulate fibronectin (FN) and alpha-smooth muscle actin (alpha-SMA), fibrogenic proteins implicated in POAG. Transforming growth factor 132 (TGF132), a fibrogenic cytokine implicated in similar to 50% cases of POAG, is also increased, and so is RhoA-associated coiled-coil-containing protein kinase 1 (ROCK-1). However, silencing of alpha-Syn in primary human TM cells reduces FN, alpha-SMA, and ROCK-1 in the absence or presence of over-expressed active TGF beta 2, suggesting modulation of FN and ROCK-1 independent of, or upstream of TGF beta 2. These observations suggest that extracellular alpha-Syn modulates ECM proteins in the TM independently or via PrPC by activating the RhoA-ROCK pathway. These observations reveal a novel function of alpha-Syn in the anterior eye, and offer new therapeutic options.

Automated summary

This study investigates the function of alpha-Syn in the anterior eye and its association with eye diseases such as glaucoma. It suggests that alpha-Syn may regulate intraocular pressure by altering the interaction between extracellular matrix and trabecular meshwork cells. These findings provide new insights for the development of novel therapeutic approaches.