Clifford W. Shults, M.D.

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Clifford W. Shults, M.D.

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Research Interests

We are interested in elucidating the pathological processes that underlie Parkinson's disease and developing new therapies for the disorder. Parkinson's disease is a degenerative neurological disorder that results in tremor, muscular rigidity, and slowness of movement. The cardinal pathological feature of the disease is the loss of the dopaminergic neurons in the substantia nigra and their axons, which project to the striatum.

In a collaborative project with Dr. Haas, we recently demonstrated that patients with early untreated Parkinson's disease have reduction in the activity of complex I of the mitochondrial electron transport chain. This finding and data from other groups suggest that mitochondrial dysfunction may be part of the process that leads to death of the nigral dopaminergic neurons in Parkinson's disease. We are working to determine the cause of the mitochondrial dysfunction. Seven genes in the mitochondrial DNA (mtDNA) encode for seven of the over forty proteins that make up complex I. We are currently utilizing denaturing gradient gel electrophoresis (DGGE) followed by sequencing to search for mutations in these seven genes in mtDNA from PD patients.

We are also working to develop treatments for PD that will slow the progression of the disorder. Coenzyme Q10 (CoQ10) is the electron acceptor for complex I and a powerful antioxidant. These characteristics suggest that it may be a useful agent to slow the progression of PD. We recently found that the level of CoQ10 was significantly lower in mitochondria from parkinsonian patients than in mitochondria from control subjects and that the levels of CoQ10 and the activities of complex I were highly correlated. We are currently evaluating the ability of CoQ10 to protect the nigrostriatal dopaminergic system in mice treated with MPTP and rats treated with 6-hydroxydopamine (two commonly used animal models of PD).

Another major focus in our work to develop treatments for PD is the study of the abilities of certain trophic factors to promote the survival of nigral dopaminergic neurons, to enhance the activity of the nigrostriatal dopaminergic system or to promote regeneration of this system. We use both in vitro and in vivo models of PD to address these issues. Using a series of models developed in the laboratory, we have recently found that brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) can protect the nigrostriatal dopaminergic system in rats that receive intrastriatal injections of 6-hydroxydopamine. We are currently extending these studies and evaluating other trophic factors.

Selected Publications

Shults, C.W., s, R.T., Altar, C.A., Hill, L.R., and Langlais, P.J. (1994). A single intramesencephalic injection of brain-derived neurotrophic factor induces persistent rotational asymmetry in rats. Exp. Neurol. 125: 183-194.

Shults, C.W., Nasirian, F., Ward, D., Nakano, K., Pay, M., Hill, L.R., and Haas, R.H. (1995). Carbidopa/levodopa and selegiline do not affect platelet mitochondrial function in early parkinsonism. Neurology 45: 344-348.

Shults, C.W., Kimber,T., and Altar, C.A. (1995). BDNF attenuates the effects of intrastriatal injection of 6-hydroxydopamine. NeuroReport 6: 1109-1112.

Haas, R.H., Nasirian, F., Nakano, K., Ward, D., Pay, M., Hill, R., and Shults, C.W. (1995). Low platelet mitochondrial Complex I and Complex II/III activity in early untreated Parkinson's disease. Ann. Neurol. 37: 714-722.

Shults, C.W., Kimber, T., and , D. (1996). Intrastriatal injection of GDNF attenuates the effects of 6-hydroxydopamine. NeuroReport 7: 627-631.