Principal Investigators:
Menek Goldstein, Ph.D.,* David Filer, Ph.D., Arnold Friedhoff, M.D., and Jing Wu, M.D.
Neurochemistry Research Laboratory* and Millhauser Laboratories, Department of Psychiatry
New York University School of Medicine

The enzyme tyrosine hydroxylase (TH) catalyses the rate limiting step of catecholamine biosynthesis, the conversion of tyrosine to DOPA, the immediate precursor of dopamine. The regulation of TH activity in the peripheral and central nervous system by extra- and intracellular signals provides the mechanism by which dopamine (as well as norepinephrine and epinephrine) secretion is modulated. A number of extracellular signals cause activation of TH via phosphorylation reactions catalysed by protein kinases.

TH is a substrate for at least three protein kinases Ð protein kinase A, calmodulin protein kinase II, and protein kinase C. Protein kinases A and C phosphorylate TH and causes kinetic changes which suggest the enzyme becomes activated. Phosphorylation-dephosphorylation is reversible and appears to be associated with activation-deactivation in physiological and pathological states. Nonphosphorylated TH is less active and may provide a reservoir of relatively inactive enzyme. Calmodulin protein kinase II phosphorylates TH without appearing to alter its kinetic activity. It is possible that phosphorylation of TH in vivo with two or more kinases can result in additive, synergistic or antagonistic effects.

Parkinson's disease results from a selective loss of dopamine-releasing neurons. Treatment by supplying L-DOPA as a compensatory source of dopamine has a number of undesired side effects which have led investigators to seek alternate therapies, such as grafting of cells into the brain. While the feasibility of using transplanted tissue to supplement or replace missing factors such as synthetic enzymes or growth factor has been established, there is a limited supply of fetal tissue and political problems associated with the use of abortus tissue.

Description of the Project:
Based on their studies of the phosphorylation of TH, Dr. Goldstein and his coworkers have used molecular genetic techniques to enhance the activity of TH by inducing genetic modification at key amino acid residues. Genetic constructs encoding variant TH enzymes will be transfected into cells which will subsequently express TH with enhanced activity. These transfected cells will provide a source of cells for transplantation to treat conditions associated with defective function of the TH enzyme.

Applications:
NYU is seeking an industrial partner to license this novel tyrosine hydroxylase technology.

Genetic constructs of TH and transfected cells expressing enhanced TH activity provide a novel therapeutic approach for treating Parkinson's and Alzheimer's diseases, and affective disorders.

Patent Status:
A patent application covering this novel tyrosine hydroxylase technology has been filed.

For further information please contact:
New York University
Industrial Liaison/Technology Transfer
650 First Avenue, New York, N.Y. 10016
Tel: (212)263-8178 Fax: (212)263-8189