Over-activation of the ROCK pathway causes cytoskeletal changes in trabecular meshwork cells (stress fibers, increased stiffness) and leads to IOP elevation, a mechanism that is now exploited by new therapeutics.1-3 Ashok et al. have a long history of investigating the role and dysfunction of the prion protein (PrPc). Their more recent interest includes PrPc's participation in iron metabolism of the posterior4 and anterior segment of the eye.5 In this study, the authors describe how PrPC induces an endothelium-to-mesenchyme-like transition and argue that this is similar to the epithelium-to-mesenchyme transition that PrPC can induce in neuronal cells through β1-integrin and Rho-ROCK activation.6-9 The authors do not explain why they think endo- and epithelial function and origins are interchangeable, however. The key pathogenic event in all prion disorders is a change in the conformation of PrPC to a β-sheet rich PrP-scrapie (PrPSc) isoform and could also be at fault here.
The authors performed an impressive array of experiments in three different species (bovine, human, murine) including PrP-knockout mice. Downregulation of PrPc activated the Rho/ROCK pathway and led to aggregation of β1-integrin, upregulation of fibronectin, collagen 1A, α-SMA and myocilin causing IOP to increase.
It is tempting to follow the line of thought by the authors that puts prions and PrPc not only central to neurodegeneration in glaucoma, but also to outflow failure. Both was already suggested by the discoverer of prions, Stanley Prusiner, in 2008 (personal communication). The authors propose a mechanism that incorrectly generalizes that POAG patients have an elevated level of matrix metallo-proteinases (MMPs), which cleave PrPc and thereby further worsen the TM outflow failure. Although there are clinicians on the team, the authors fail to realize that the same MMPs (MMP 2 and 9) they believe to be important in their model of IOP elevation, are actually therapeutically upregulated by laser trabeculoplasty to lower IOP.10 Patients with prion diseases are also not known to have elevated eye pressures (but do more frequently get tonography11), even though prions are typically present in ocular tissue.12 Conversely, glaucoma patients do not have more PrPc.13