The Morris K. Udall Center of Excellence for Parkinson's Disease Research at the University of Virginia

Director: James P. Bennett, Jr, M.D., Ph.D.

Title: Mitochondrial Etiologies of Parkinson’s Disease

 

Central Theme

The central theme of our Udall Center remains that of mitochondrial involvement in pathogenesis of sporadic Parkinson’s disease, the variant that afflicts ~90% of sufferers. We have expanded our theme to focus increasingly on translational diagnosis and therapy development.

 

Center Structure

Our Center has three Projects and three Cores. The Projects are headed by Rod Capaldi (MitoSciences, Eugene OR), Patricia (Pat) Trimmer (UVA, Charlottesville VA) and Jim Bennett (UVA, now Virginia Commonwealth University, Richmond). The Capaldi Project is centered around development of novel metabolomic biomarkers for PD. They have developed an ELISA that will assay levels of 47 different enzymes related to intermediary and mitochondrial metabolism. The goal is to determine if such an ELISA system provides a metabolomic signature for PD and the responses of PD patients to therapeutics. The Trimmer Project studies Lewy body (LB) formation in living cells derived by clonal selection of LB-forming PD cybrids. Using a mechanical cloning strategy, PD cybrid lines have been produced that have ~20-35% of cells spontaneously forming LB’s. The Trimmer Project also is developing low level near-infrared laser light as energy-enhancing therapy for PD. Laser therapy is in Phase III testing in humans with stroke, so it is available for testing in PD patients. The Bennett Project collaborates with a local biotech company to develop mitochondrial gene therapy. Accumulating evidence shows that PD brain mitochondria are deficient in respiratory proteins, and the therapy being developed in the Bennett project stimulates mitochondrial biogenesis and increases respiratory protein levels. Our Cores include a Cybrid Core, where the LB clones are made and passed, a Molecular Core where all qPCR and molecular work is performed, and an Administrative Core.

 

Recent Significant Advances

Project 1: Development of a 47 protein ELISA to allow assaying metabolonic signature of PD tissues.

Project 2: Successful cloning of and marked enrichment in spontaneous LB production in PD cybrids. Demonstration of enhanced mitochondrial function in PD cybrids following near-IR laser illumination.

Project 3: Demonstration of successful transfer of exogenous mtDNA into mitochondria of cells, including PD cybrids, resulting in improvement of respiration and stimulation of mitochondrial biogenesis.

 

Available Resources

Cybrid cells from Parkinson’s disease and control subjects

 

Plans for the coming year

1. Test metabolomic ELISA in PD and CTL brain samples
2. Test laser light therapy in rodent PD models
3. Use FRAP to define kinetics of spontaneous LB formation
4. Demonstrate delivery and expression of exogenous mtDNA in nigral neurons
5. Test recovery of mtDNA and motor function in rodent PD models following mitochondrial gene therapy

 

Select Recent Publications

Trimmer, PA, Bennett, JP, Jr The cybrid model of sporadic Parkinson’s disease. Exp Neurol 2009 218:320-5.

Marusich MF, Murray J, Xie J, Capaldi RA. Novel antibody-based strategies for the rapid diagnosis of mitochondrial disease and dysfunction. Int J Biochem Cell Biol. 2009 41:2081-8.

Murray J, Capaldi RA. Screening for the metabolic basis of neurodegeneration: developing a focused proteomic approach. Ann N Y Acad Sci. 2008 1147:348-57.

Trimmer PA, Schwartz KM, Borland MK, De Taboada L, Streeter J, Oron U. Reduced axonal transport in Parkinson's disease cybrid neurites is restored by light therapy. Mol Neurodegener. 2009 4:26.

Borland MK, Mohanakumar KP, Rubinstein JD, Keeney PM, Xie J, Capaldi R, Dunham LD, Trimmer PA, Bennett JP Jr. Relationships among molecular genetic and respiratory properties of Parkinson's disease cybrid cells show similarities to Parkinson's brain tissues. Biochim Biophys Acta. 2009 1792:68-74.

Keeney PM, Quigley CK, Dunham LD, Papageorge CM, Iyer S, Thomas RR, Schwarz KM, Trimmer PA, Khan SM, Portell FR, Bergquist KE, Bennett JP Jr. Mitochondrial gene therapy augments mitochondrial physiology in a Parkinson's disease cell model. Hum Gene Ther. 2009 20:897-907.

 

Public Health Statement

Parkinson’s disease (PD) is a major brain degenerative disease of adults that afflicts 1-1.5 million Americans and arises for unclear reasons. We are pursuing the concept that a major contributor to appearance and progression of Parkinson’s disease is a loss of energy production by mitochondria and an increase in oxygen free radical damage. This decline in energy producing capacity is present in mitochondria from brains of PD subjects and arises for unclear reasons. Our Udall Center group is developing an antibody-based test (ELISA) to demonstrate loss of energy producing proteins in PD tissues, with the hope that this test might be used to diagnose persons with PD before they exhibit clinical symptoms. We are exploring the mechanisms that underlie formation of a specific type of aggregated protein “clump” inside PD brain neurons, called a Lewy body (LB). LB’s are present in brains of all PD patients, and it is not clear how they form or whether they are detrimental or beneficial for the life of a nerve cell. Our initial findings suggest that LB’s may be beneficial. We are also developing therapies to improve energy production in PD brain cells. One of these approaches uses external irradiation with laser light. The type of laser used can penetrate the skull and produce effects on brain tissue in living animals and persons. We hope to develop laser light to the point of human testing in PD in 1-2 years. Finally, we are developing a novel gene therapy protein that can stimulate an increase in mitochondrial mass and energy production in brain and other tissues. This protein therapy appears to be safe and both increases energy production and lowers oxygen free radical damage in brain. We hope to introduce it to human use in 3-5 years. Thus, the overall goal of our Udall Center is to characterize the energy metabolism problems in PD brain and develop therapies to correct the energy deficiency. During the past year we have made significant progress in both areas.