Autophagic Dysfunction in Exfoliation Glaucoma

Project Summary

Our goal is to reverse the effects of exfoliation syndrome (XFS), the leading identifiable cause of open-angle glaucoma.  

Like recent work in studies of several other age-related diseases, such as age-related macular degeneration (AMD) and Alzheimer’s disease, our lab has found that XFS cells have a dysfunction in the cellular machinery that would normally degrade protein aggregates (autophagy and lysosomes) and in the organelle that produces the energy needed for the cellular degradation (mitochondria). Our hypothesis is that these defects play a role in generating the accumulation of cellular waste that becomes toxic. We are growing cells from tissue derived from XFS patients who have undergone glaucoma surgery to relieve pressure in the eye. These cells are called tenon fibroblasts. Since one of the major challenges of XFS research has been a lack of model systems for experimental purposes, our patient-derived cells provide a wealth of opportunity to identify critical pathways that are disrupted in XFS-affected cells and to use these patient cells to screen for molecules that can reverse lysosomal and mitochondrial dysfunction.

Specifically we will utilize the tenon fibroblast model system to 1) distinguish the proteomic profiles specific to XFS cells and the autophagic defect; 2) test that the autophagic defect in these cells is the reason for the build-up of toxic aggregates as we have hypothesized and 3) screen these patient-derived cells with autophagy-stimulating drugs to identify compounds that may reverse the dysfunction. Together these approaches will drive towards our goal of reversing XFS pathology in patients.