The Role of Novel Protein Tyrosine Phosphatases in Development and Maturation of Neural Pathways Implicated in Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
Wesleyan University
Investigators Name
Naegele, Janice, PhD

Different lines of research have suggested that Tourette Syndrome (TS) results from a malfunction within neural pathways involving the basal ganglia. Although some abnormalities in these pathways have been found at the anatomical level, it is likely that a more significant biochemical abnormality is present, which has yet to be identified. Recently, Singer et al. (1990) provided an hypothesis to account for the symptoms of TS, based on findings of reductions in second messenger molecules in the cerebral cortex of adult TS patients. Abnormalities in these or other molecules involved in intracellular signalling within the basal ganglia could produce the diverse neurochemical deficiencies that are found in TS patients. Our work in the basal ganglia focuses on a class of intracellular signalling molecules termed protein tyrosine phosphatases. Extracellular signals, such as transmitter molecules or growth factors, trigger intracellular responses through a variety of mechanisms; one is through the addition or removal of phosphate groups on serine, threonine or tyrosine residues on molecules involved in the intracellular signalling cascade. A wide variety of proteins in the basal ganglia are regulated by phosphorylation, including neurotransmitter and growth factor receptors, cytoskeletal proteins, and ion channels. Tyrosine phosphorylation in particular, is known to mediate critical events during nervous system development. The high level of tyrosine phosphorylation in the developing brain suggests that enzymes involved in the addition of phosphates (tyrosine kinases) or removal of phosphate groups (tyrosine phosphatases) might be particularly active at these times. We have indentified and characterized a tyrosine phosphatase that is highly enriched in the striatum. This tyrosine phosphatase has been designated “STEP”, for “striatal enriched phosphatase”, and additional family members have now been isolated. The STEP family of tyrosine phosphatases are within striatal neurons receiving dopamine-containing nerve terminals. These neurons are part of a circuit that includes subsets of neurons in the cerebral cortex, striatum and substantia nigra. The studies supported by the Tourette Syndrome Association are designed to investigate whether development of dopaminergic innervation to the striatum causes maturation of signalling pathways involving STEP and tyrosine phosphorylation. This support will allow us to clarify the factors regulating the maturation of cortical-striatalnigral circuits during normal development. Janice R. Naegele, Ph.D. Wesleyan University, Middletown, CT Award $25,000 Tourette Association of America Inc. – Research Grant Award 1994