Targeted OCRL Modulation Reduces Steroid-Elevated IOP
Translational Vision Science & Technology
Open-angle glaucoma can be induced by prolonged use of topical glucocorticoids and involves elevated intraocular pressure (IOP) with outflow resistance and abnormal trabecular meshwork (TM) function. Kowal et al. have used an optogenetic approach in TM to regulate 5-phosphatase (5ptase) OCRL, which contributes to regulating phosphatidylinositol 4,5-bisphosphate (PIP2). In a subsequent study, they applied this system with the intent of reversing compromised outflow in a steroid-induced murine model of ocular hypertension. They found that blue-light stimulation caused CRY2-OCRL-5ptase to translocate to plasma membrane and cilia in TM cells, which normalized IOP and outflow activity. Moreover, in cultured human TM cells, they noted that optogenetic stimulation reduced the aberrant actin structures caused by dexamethasone.
For this study, the authors induced elevated IOP by subconjunctival injection of dexamethasone into wild-type mice. Following this, they injected adeno-associated viruses containing optogenetic modules of CRY2-OCRL-5ptase and CIBN-GFP into the anterior chamber. Four weeks after incubation, they measured IOP by tonometry and assessed outflow facility by perfusion analysis. In a separate evaluation of actin structures, they explored theeffects of light stimulation on human TM cells exposed to dexamethasone.
As expected, the dexamethasone raised IOP and lowered outflow facility in the mice. Optogenetic constructs were expressed in the TM of mouse eyes, and light stimulation caused CRY2-OCRL-5ptase to translocate to the plasma membrane (CIBN-CAAX-GFP) and cilia (CIBN-SSTR3-GFP) of TM cells, which rescued the IOP and outflow facility. In human cells, the aberrant actin structures were minimized by optogenetic stimulation.
Subcellular targeting of inositol phosphatases to remove PIP2 is “a promising strategy to reverse defective TM function in steroid-induced ocular hypertension,” said the authors. Their findings support the hypothesis that cytoskeletal alterations and formation of cross-linked actin networks (CLANs) are responsible for the abnormal out-flow facility and IOP observed in mice. They concluded that their study offers a new framework for a therapeutic approach based on signaling and emphasized the need to identify precise pathways that lead to formation of OCRL-dependent CLANs.
The original article can be found here.