For more than 30 years, administration of L-DOPA has been the treatment of choice for patients with Parkinson's disease (PD), a disease primarily of the elderly. Prolonged therapy with L-DOPA, however, is associated with disruptive motor fluctuations, and loss of effectiveness with time. There has been much discussion as to why L-DOPA treatment loses effectiveness, but the enzyme that forms dopamine (DA) from L-DOPA, aromatic L-amino acid decarboxylase (AAAD), is often left out of this debate. There is now overwhelming evidence that AAAD, required for the biosynthesis of DA, is regulated in the brain. AAAD activity undergoes short- and long-term changes in vivo, and enzyme activation and induction are involved. Enzyme modulation is achieved via neurotransmitter receptors and second messenger-dependent pathways. Short-term activation is correlated with phosphorylation of the enzyme. In addition to its theoretical interest, regulation of AAAD might have ramifications for L-DOPA treatment in PD. Pharmacological enhancement of AAAD, the controlling step for the formation of DA from exogenous L-DOPA, may improve the clinical response to L-DOPA; while, uncontrolled fluctuation of AAAD activity may explain the """"""""on-off"""""""" phenomenon. There are three aims: #1 . To Characterize the Role of Neurotransmitter Receptors in the Modulation of AAAD; #2. To Evaluate the Role of Aging and Severity of Dopaminergic Lesion on AAAD Modulation; and #3. To Investigate the Phosphorylation AAAD. The studies focus on the AAAD of the dopaminergic nigrostriatal neurons of young, mature and old mice, as well as on mice lesioned with MPTP. They expand our work in identifying classes of neuroactive drugs that increase AAAD activity and have the potential for clinical application. In addition to dopaminergic receptors, there is now evidence that glutamate, nicotinic and serotonergic receptors might modulate AAAD.
Aim #1 investigates these neurotransmitter systems and their possible role for AAAD modulation, and evaluates whether increasing AAAD activity results in more DA being formed from administered L-DOPA. PD is common in older people and worsens with age as more dopaminergic neurons degenerate.
Aim #2 is a study of AAAD and how aging and degeneration of dopaminergic neurons influences the ability to modulate enzyme activity. Short-term modulation of AAAD is, in part, controlled by phosphorylation.
Aim #3 utilizing targeted in vitro, in site, ex vivo and site-directed mutagenesis experiments, continues our efforts to identify the kinases involved, investigates the site(s) of phosphorylation and their importance for activity, and explores how aging and severity of the lesion affect AAAD phosphorylation. This proposal has direct clinical relevance for PD, as it addresses the functionality of an enzyme absolutely required for successful L-DOPA therapy.
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