Grant: Project Grant

Sight is essential for humans to gather critical information about their surroundings. The fear of going blind has been reported to be more powerful than that of having cancer or heart disease. Glaucoma is the leading cause of irreversible blindness, affecting >60 million people worldwide. There is no cure for glaucoma and current therapies are inadequate. Loss of vision in glaucoma results from the death of retinal ganglion cells, the neurons that convey visual information from the retina to the brain. High intraocular pressure is the most significant risk factor for developing the disease, but the mechanisms by which ocular hypertension damages retinal ganglion cells are unknown. A major roadblock towards developing effective therapeutics for glaucoma is that very little is known about the early pathological alterations that lead to retinal ganglion cell dysfunction and death. Our recent work has identified a new and intriguing role for tau, a microtubule binding protein implicated in Alzheimer's disease, in ganglion cell neurodegeneration. We showed that tau undergoes substantial alterations early in glaucoma including abnormal phosphorylation, aggregation and missorting. In this application, we will determine the role of tau in the earliest pathological changes in glaucoma, namely retinal ganglion cell dendrite retraction and anterograde axonal transport impairment. This project is unique and timely because it will provide new insight into the molecular mechanisms that govern glaucoma pathogenesis, and it will serve as a springboard to identify new therapeutic targets and potential diagnostic tools for this blinding disease.