New Scholar Award in Aging
Michael Gordon Kaplitt, M.D., Ph.D.
Weill Medical College of Cornell University

Effect of PTEN Anti-Oncogene on Age-Related Neurodegenerative Disorders

Progressive loss of neurons in the brain is a hallmark of many neurodegenerative disorders, including Alzheimerís disease and Parkinsonís disease. The only known risk factor for the majority of such patients is aging. Nonetheless, most people do not develop these disorders during aging, so other factors must contribute to or predispose towards development of aging-associated neurodegenerative disorders. Several protein pathways and interactions within neurons have been identified which are associated with neurodegenerative disorders. Anti-oncogenes are genes which prevent cells from transforming into cancerous cells, and loss of one or more anti-oncogenes is often found in cancer cells. These genes also influence a variety of functions within normal cells, including normal neurons. We have recognized several possible areas of intersection between anti-oncogene pathways and pathways associated with neurodegenerative disorders. Since malignant primary brain tumors are also associated with aging, but these patients seem to rarely have neurodegenerative disorders as well, we have hypothesized that anti-oncogenes may prevent tumor formation but may increase susceptibility of neurons to aging-associated neurodegenerative disorders. This hypothesis has been strengthened by the recent finding that increased activity of the p53 anti-oncogene in mice results in more rapid aging, including reduction of lifespan, organ wasting and earlier-onset osteoporosis.

We are currently focusing upon the relationship between the PTEN anti-oncogene and development of aging-associated neurodegenerative disorders. PTEN is among the most frequently inactivated genes found in human malignant brain tumors. Some of the cellular functions known to be influenced by PTEN have also been found to influence development of pathologies associated with Alzheimerís disease. PTEN pathways may also increase susceptibility of dopamine producing neurons in the brain to damage or toxicity, and loss of these cells is the key defect in Parkinsonís disease. Using neuron-like cells in tissue culture, we have generated preliminary evidence that overproduction of PTEN can result in cellular changes found in Alzheimerís disease and Parkinsonís disease. We are currently using our cellular systems to further explore these pathways by both overproducing PTEN and by blocking its production. Our laboratory also helped pioneer the use of modified viruses for gene therapy or gene transfer in the brain, and we are using this gene therapy technology to manipulate the production and/or activity of PTEN in the brain of normal adult animals. This will permit exploration of the influence of PTEN upon learning and memory defects associated with Alzheimerís disease, as well as upon sensitivity of dopamine-producing neurons to toxicity in standard animal models of Parkinsonís disease. We hope that information generated from these studies will help us to develop new drug or gene therapies focused upon preventing any deleterious effects of these anti-oncogene pathways on the aging brain.

Contact Dr. Kaplitt.