Age-Related Macular Degeneration: New Targets for Novel Therapies From the Glia Research Laboratory

Age-related macular degeneration (AMD) is the most common cause of visual impairment in older adults over the age of 60. There are no effective treatments available to stop the progression of the disease and no cure once it manifests (although treatments aimed at neovascularization in the wet form of the disease can slow progression, more than 90 percent of AMD in the United States is of the dry type). Gaps still exist in the understanding of the pathophysiology and mechanisms responsible for activating and driving the progression of disease.

The Glia Research Laboratory in the Department of Ophthalmology, led by Debasish Sinha, PhD, is exploring how the mechanistic traits and role of the retinal pigmented epithelium (RPE) and 
its corresponding cellular lysosome functions, specifically autophagy and phago cytosis changes and dysregulation. These processes are controlled by signaling pathways arising from the protein complex known as mTORC1 — the mechanistic (or mammalian) target of rapamycin complex 1.

Dr. Sinha is the Jennifer Salvitti Davis, MD, Chair in Ophthalmology Research, and a professor of ophthalmology, cell biology, and developmental biology at the University of Pittsburgh School of Medicine. As principal investigator in the Glia Research Laboratory, Dr. Sinha’s primary research goal is to better understand the mechanisms that regulate autophagy and phagocytosis in the lysosomes of the RPE cells, the dysregulation of which is a factor in the early stages of development of AMD.

The RPE and AMD

The RPE is a single layer of cells between the retina and the choroid. The RPE is critical to the health of the photoreceptors in the retina. Photoreceptors continually grow new outer segments. As these outer segments are renewed, the terminal portions become damaged and are released into the space between the photoreceptors and RPE. The RPE cells must engulf this material and digest it through phagocytosis. Phago-cytosis recycles the constituent molecules from the damaged photoreceptor portions back to the retina so the photo receptors can manufacture new outer segments. 
Autophagy, a process in which damaged proteins or organelles within the cell are collected, degraded, and removed, is also critical in RPE cells.

“We know that when the RPE lose these functions they not only can die, but they also can damage the photoreceptors, leading to loss of vision if the process continues unchecked,” says Dr. Sinha.
Early stages of AMD are characterized by the accumulation of drusen between the RPE and the retina, and dysregulation and degeneration of the RPE drive this accu-mulation of drusen due to changes in the processes of autophagy and phagocytosis in the RPE lysosomes responsible for removing damaged cellular materials.

“The RPE cells are responsible for, among other things, protecting the photoreceptors from damage. It is when these processes go awry that early AMD damage begins to accrue,” says Dr. Sinha.

AMD and mTORC1

The mechanistic target of rapamycin complex — mTORC1 — is responsible for a variety of protein translational processes in the human body, mainly related to aspects of growth and metabolism. Because mTORC1 regulates several processes, targeting it directly by modifications or inhibitory processes can lead to severe toxicities and unintended consequences. Because of the systemic nature of mTORC1, a potential way to avoid these toxicities is to stimulate or stabilize the signaling pathway itself without exogenous molecules.

Dr. Sinha’s work focuses on the unique proteins that regulate the assembly of the mTORC1 signaling pathway in the RPE cells. These proteins play an important role in the complex process of recruiting mTORC1, which is known to be a negative regulator of autophagy, to the lysosomal surface of the RPE where it influences lysosomal function. “This is a novel approach to rejuvenating lyso somal function of the RPE that could circumvent the side effects and toxicities that result from directly targeting mTORC1 to develop therapeutic targets in AMD. One of our research priorities is to identify upstream and downstream targets to modulate mTORC1 activity. In theory, this would allow us to regain control over or other wise regulate autophagy in the lysosome of the RPE cells,” says Dr. Sinha.

For Further Reading

Wang J, Zibetti C, Shang P, Sripathi SR, Zhang P, Cano M, Hoang T, Xia S, Ji H, Merbs SL, Zack DJ, Handa JT, Sinha D, Blackshaw S, Qian J. ATAC-Seq Analysis Reveals a Widespread Decrease of Chromatin Accessibility in Age-Related Macular Degeneration. Nat Commun. 2018; 9(1): 1364.

Sinha D, Valapala M, Shang P, Hose S, Grebe R, Lutty GA, Zigler Jr JS, Kaarniranta K, Handa JT. Lysosomes; Regulators of Autophagy in the Retinal Pigmented Epithelium. Exp Eye Res. 2016; 144: 46-53.

Ghosh S, Shang P, Yazdankhah M, Bhutto I, Hose S, Montezuma SR, Luo T, Chattopadhyay S, Qian J, Lutty GA, Ferrington DA, Zigler Jr JS, Sinha D. Activating the AKT2/NFkB/LCN-2 Axis Elicits an Inflammatory Response in Age-Related Macular Degeneration: Lipocalin-2 as an Indicator of Early AMD. J Pathol. 2017; 241(5): 583-588.

Zigler Jr JS, Sinha D. bA3/A1-crystallin: More Than a Lens Protein. Prog Retin Eye Res. 2015; 44: 62-85.

Shang P, Valapala M, Grebe R, Hose S, Ghosh S, Bhutto I, Handa JT, Lutty GA, Lu L, Sergeev Y, Puertallano R, Zigler, Jr. JS, Xu GT, Sinha D. The Amino Acid Transporter SLC36A4 Regulates the Amino Acid Pool in Retinal Pigmented Epithelial Cells and Mediates the Mechanistic Target of Rapamycin Complex 1 Signaling. Aging Cell. 2017; Jan 13. doi: 10.1111/acel.12561.