Parkinson’s Disease (PD) is an especially pernicious chronic neurodegenerative disease affecting nearly 1 in 100 people over age 60. Affected individuals slowly lose their independence as they become unable to move and balance themselves, with some patients developing cognition problems including dementia. The molecular underpinnings of this disease are becoming clearer thanks to the work of Tim Greenamyre, M.D., Ph.D., the Love Family Professor, Vice Chair of Neurology, Chief of the Movement Disorders Division of the Department of Neurology at the University of Pittsburgh School of Medicine, and the Director of the Pittsburgh Institute for Neurodegenerative Disorders (PIND) and the American Parkinson Disease Association Center for Advanced Research at the University of Pittsburgh.
Scientists have appreciated that cells producing the neurotransmitter dopamine within a specific region of the brain – the substantia nigra – fail over time, resulting in clinical symptoms. They also appreciate that PD likely results from some combination of genetic and environmental exposures, with pesticides being a primary culprit. But the exact molecular steps within cells that lead to PD has remained mysterious until quite recently. Over 25 years, physician-scientist Greenamyre has developed a rat model of PD that has revealed specific biological changes within cells that ultimately render them unable to function. After exposure to the pesticide rotenone, nerve cells within rats undergo changes in their mitochondria, the energy-producing factory of cells. Greenamyre has identified two specific alterations – problems with iron regulation and a buildup of a chemical called alpha synuclein – that are also seen in post-mortem tissue taken from patients with PD. His lab is currently exploring the development of PD-related dementia in rats exposed to short doses of rotenone to understand the molecular changes associated with this clinical course, information that could funnel back into future patient treatments.
Greenamyre has been widely honored for his work in PD and other neurodegenerative disorders. He chaired the research grants subcommittee of the Huntington’s Disease Society of America, was a member of the NIH Parkinson’s Disease Research Agenda Planning Committee, the Parkinson’s Disease Implementation Committee and the Neurological Sciences and Disorders B Study Section of the National Institute for Neurodegenerative Diseases and Stroke. Greenamyre also chaired the Scientific Advisory Committee of the Parkinson Study Group and is a member of the Scientific Advisory Board of the Michael J. Fox Foundation, the American Parkinson Disease Association, and the Parkinson’s Disease Foundation. He has been listed as one of the “Best Doctors in America” since the 1990s and was elected to the Association of American Physicians in 2015.
He is the Editor-in-Chief of the scientific journal, Neurobiology of Disease, and of MedLink Neurology, and is a Consulting Editor for the Journal of Clinical investigation. In October 2004, he delivered the Presidential Lecture at the Annual Meeting of the Society for Neuroscience.
Greenamyre received his bachelor of science from Michigan State University and his MD and PhD from the University of Michigan. After his neurology residency at the University of Michigan, he joined the University of Rochester in 1990, then in 1995 became faculty at Emory University before coming to the University of Pittsburgh in 2004.
“Designing a Gene Therapy for Parkinson’s Disease”
One in four Americans will suffer from a neurodegenerative disease such as Alzheimer’s Disease, PD, or Huntington’s Disease. Aging is the most important risk factor, with nerve cells being unable to repair themselves or self-destruct effectively when appropriate. Problems with the immune system and the mitochondria also appear to be common areas for dysfunction in neurodegenerative disorders.
Current therapies for these diseases are in short supply, and most are ineffective after a period of time. One of the most promising areas to explore, according to Greenamyre, is gene therapy. He proposes to use therapeutic DNA to target host DNA sequences to reduce the expression of a toxic, mutant protein, in this case alpha-synuclein. This protein has been shown to build up in toxic excess in the brains of animals and humans with PD. Such a “precision medicine” approach would revolutionize the treatment of these neurodegenerative diseases. Harmless viruses that are converted into gene shuttles would be used to convey DNA-based therapeutics directly to affected brain regions in a neurosurgical procedure.
To accomplish this goal, Greenamyre hopes to partner with neurosurgeons and laboratory scientists.
To the left is an image of the buildup of alpha-synuclein in the nerve cells of the subtantia nigra. Greenamyre’s team already has shown that reducing alpha-synuclein in rats protects them from developing PD after exposure to rotenone. The next step is constructing a gene therapy that can be used to down-regulate production of this protein in the brain.