Towards therapeutic correction in disorders of neurotransmitter synthesis. Modulation of tyrosine hydroxylase stability and localization

Tyrosine hydroxylase (TH) is decreased in neuropsychiatric disorders such as Parkinson's disease and schizophrenia, and in genetic diseases known as TH deficiencies and manifested by L-dopa-responsive dystonia. In all these disorders, production of catec holamine neurotransmitters is compromised. TH is activated and stabilized by phosphorylation-dependent binding to 14-3-3 proteins, which also modulates TH's subcellular distribution between cytosol and membranes. Recent results from Prof. Aurora Martinez' s lab at the Department of Biomedicine, University of Bergen, indicate that in healthy situations, the binding of TH to membranes occurs when TH is loaded onto 14-3-3g. The TH:14-3-3 interaction maintains TH activity and stability, and avoids the harmful direct binding of the enzyme to membranes. The use pharmacological chaperones for correction of misfolding of mutant TH proteins, as well as for the modulation of TH activity and stability through interaction with 14-3-3 and membranes, is an important th erapeutic approach for correction of genetic TH deficiencies and neurodegenerative diseases. The proposed project aims to study the activity and stability of TH, its subcellular localization per se and in relation to 14-3-3 in different physiological co nditions and pharmacological situations. To this end microscopy and proteomic characterizations will be carried out in neuronal cellular models. The project is integrated in a translational research program in the group of Prof. Martinez, investigating mo lecular mechanisms behind misfolding of TH and membrane disruption, and alternative therapies for the stimulation of neurotransmitter synthesis. The group maintains specific infrastructure and expertise required in the present project, including screening , biophysical and cellular expertise and also requires advanced imaging and proteomic methodology for quantification and colocalization of proteins, available through FUGE-platforms (PROBE and MIC).