News & Research

Penn State University College of Medicine Hershey, Pennsylvania

Role of ubiquitin in diabetes-induced degradation of retinal synaptic proteins

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Complications\Ocular, Complications\Neuropathy

Type of Grant: Basic Science

Project Start Date: July 1, 2009

Project End Date: June 30, 2012

Research Description

This project focuses on the cause of vision loss in diabetic retinopathy and aims to understand diabetes-induced degeneration of neurons in the retina. Earlier studies showed that retinal neuronal death is accelerated in diabetic rats. New data show that the connections between neurons, called synapses, degenerate more rapidly that expected. Some of the proteins within synapses help to store and release neurotransmitters, which carry signals between neurons by moving across synapses. These proteins are rapidly depleted by diabetes. The project will determine whether this depletion involves increased activity of a protein-disposal mechanism in neurons called the ubiquitin-proteasome system.

This is like a recycling plant inside the cell that rapidly breaks down proteins into their constitutive parts for reuse. It works by tagging unwanted proteins with a marker called ubiquitin. The tagged protein moves to a proteasome, which is a group of enzymes assembled into a series of ring structures like a stack of doughnuts. As the tagged protein moves through the hole in the center of the stack of enzymes it gets broken down. This system degrades proteins very rapidly and ensures that unwanted proteins don't accumulate inside the cell. This project will determine if the depletion in synaptic proteins in the retinas of diabetic rats is due to an abnormal increase in the activity of the ubiquitin-proteasome system. The results will show how diabetes causes the neurons of the retina to fail, leading to loss of vision; and identify potential drug-targets to prevent vision loss in diabetes.

Reseacher Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?  

This project will examine one of the possible mechanisms of vision loss in diabetic retinopathy, a complication of diabetes that can cause blindness. We have previously shown that diabetes leads to reduction in the amount of certain proteins that are required for transmission of information between the neurons of the retina. These proteins, called pre-synaptic vesicle associated proteins, exist most abundantly in the tiny connections between neurons, called synapses, which are used to transfer electrochemical impulses and can be thought of much like the transistors in a computer. When these synaptic proteins are depleted there can be a reduction in the amount of information that is transferred between the neurons.

The project will determine whether the depletion of synaptic proteins in the retinas of diabetic animals is due to an abnormally high rate of protein degradation through the ubiquitin-proteasome system, which works like a recycling plant in the cell by targeting specific proteins for degradation and then breaking them down into small pieces so they can be reused. We will examine the possibility that retinal synaptic proteins are degraded at a faster rate during diabetes, with the ultimate plan of determining the major mechanism for the reduction. Once this mechanism has been found we will be able to identify new targets for the development of pharmacological inhibitors, in the hope that a novel drug can be found to protect against vision loss in the early stages of diabetic retinopathy.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

This project will help people with diabetes in the future because it will provide a better understanding of diabetic retinopathy, and help develop new ways to prevent the disease from developing, or to slow the rate of vision loss in people who already have diabetic retinopathy.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts? 

My research has been entirely focused on the mechanisms of how diabetes causes vision loss and retinal degeneration since 1995. I have always been most interested in research questions that have a direct relevance to a specific disease, with the goal of contributing valuable information that will one day lead to improvement in the treatment and health care for those people suffering from the disease. My primary research interest has always been in chronic degenerative diseases of the nervous system, because these have such a high impact on individuals and our whole society.

These types of diseases tend to have a very protracted time course, leading to chronic debilitation, which is so costly and affects patients and their families for their entire lives.  Diabetes is such a prevalent disease because it affects so many people and reduces their quality of life, in some cases dramatically, so it is a very worthy area for further research. This award will help to continue the ongoing research on neurodegeneration in diabetic retinopathy.

In what direction do you see the future of diabetes research going? 

I expect that diabetes will continue to be one of the primary diseases that biomedical research focuses on, since it is so common and so costly in terms of human suffering, apart from the enormous socioeconomic costs.  The need for research on diabetes may expand as greater numbers of our population develop the disease and its complications. While education and awareness about diabetes are increasing all the time, I believe that the most effective therapies will be pharmacological interventions. I see a time in the future when the complications of diabetes will be prevented with one or more drugs, while there is also hope that the disease itself will be cured using new cutting-edge technology like gene therapy, stem cell therapy, or even new technologies to create artificial pancreatic cells.