CNS Drug Discovery & Therapy (Track)


Aurora Martinez

Department of Biomedicine, University of Bergen, Bergen, Norway


Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of dopamine, noradrenaline, and adrenaline. Primary inherited defects in TH have been associated with L-DOPA responsive dystonia (DRD) and infantile parkinsonism. We have formerly demonstrated that both tetrahydrobiopterin (BH4) and a pharmacological chaperone (compound III; a small compound that rescues misfolded proteins) stabilize human TH as well as mutants associated with DRD (Calvo, et al., 2010; Thöny, et al., 2008) in vitro. Supplementation of mice with either BH4 or compound III increases total TH activity and protein in mouse brain. This increase was not accompanied by changes in steady-state brain dopamine levels and monoamine neurotransmitter metabolites DOPAC and HVA. The failure to observe an increase in dopamine, despite a higher total TH activity, might reflect strict enzyme regulation in vivo. Nevertheless, we anticipated that increased TH activity would lead to increased dopamine synthesis in certain states including pathological conditions, and have therefore investigated this possibility using a heteroallelic orthologous mouse model (ENU1/2) of phenylketonuria (PKU), where synthesis of neurotransmitters is compromised due to high concentration of L-Phe in brain ([Phe] disposal is significantly reduced in ENU1/2 mice as compared with their normal C57BL/6 counterpart). Supplementation with either BH4 (50 mg/kg/day) or compound III (8 mg/kg/day), for 10 days, increases TH activity and protein in ENU1/2 mice. Thus these treatments might be promising as potential therapies for disorders associated with TH misfolding and other deficiencies in dopaminergic neurotransmission. However, since both BH4 and compound III also affect the steady-state levels of the other BH4-dependent aromatic amino acid hydroxylases, it is important to find other more specific compounds for TH. Hence, we are at present complementing experimental and virtual screening strategies to find drug-like compounds which are more effective both to stabilize TH and its mutants, as well as to protect towards the time-dependent loss of TH activity. So far we have identified about 10 compounds ready to be tested in vivo for their pharmacological chaperone potential in TH-deficient mice models.