Targeting Tyrosine Hydroxylase to Improve Bradykinesia

Abstract

The product of the tyrosine hydroxylase (TH) catalyzed conversion of L-tyrosine, L-DOPA, has been the gold standard for treating Parkinson’s disease (PD) for half a century (Birkmayer and Hornykiewicz, 1961; Calne and Sandler, 1970). While L-DOPA therapy can improve locomotor disability in PD, it does not arrest the course of PD progression. Furthermore, dyskinesia is a debilitating side-effect of L-DOPA use over time. There have been promising results from preclinical and clinical studies for PD treatment. In fact, preclinical work indicates that enhanced TH protein expression accompanies locomotor improvements. Furthermore, the fact that L-DOPA treatment alone can improve locomotor dysfunction in PD is, by itself, a testimony to the critical importance of TH function in the nigrostriatal pathway for maintaining the capacity for initiating and maintaining normal locomotor activity. Clearly the major loss of TH, the rate-limiting enzyme of DA biosynthesis, in PD diminishes the capacity for locomotor activity. Surprisingly, efforts to treat PD symptoms have not deliberately focused on restoration of TH protein or its activity. Nonetheless, the rationale to focus on improving TH function to reduce the motor deficits associated with PD has been developed serendipitously over the past decade. Notably, research studying the neurobiological basis of how growth factors can improve locomotor activity in both Parkinson’s disease and aging-related bradykinesia has revealed that increasing TH protein and its activity, through enhanced phosphorylation, should be a central feature of therapies intended to restore locomotor function in PD and aging-related Parkinsonism. Furthermore, these studies have led to the prospect that increasing DA tissue content in the substantia nigra alone could improve locomotor activity. Taken together, the possibility that increasing TH protein and activity in the substantia nigra could, by itself, restore locomotor deficits must be explored and no longer ignored.