Changes in molecular mechanisms of dopamine signaling in advanced Parkinson's disease

About This Grant

Project Summary Parkinson’s disease (PD) is primarily characterized by symptoms caused by loss of midbrain dopamine (DA) cells that modulate the function of striatal neurons. DA replacement with L-Dopa is effective to control symptoms for some time, but as disease progresses the overall efficacy of L-Dopa declines and, as a result, patients suffer increasing disability. The mechanisms underlying this evolution of DAergic therapy are poorly understood, although there is evidence for maladaptive plasticity of striatal projection neurons (SPNs). Such maladaptive plasticity involves changes in DA signaling pathways that are mediated by the second messengers, i.e., cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). A critical regulation of cGMP and cAMP levels derives from their catabolic enzymes, the phosphodiesterases (PDEs). However, how these cyclic nucleotides are regulated in direct and indirect SPNs remains unknown. These knowledge gaps are critical limitations to unveil the mechanisms for altered SPN responses to long-term DA replacement therapy. This new study is focused on the dysregulation of cyclic nucleotides that develop in SPN subtypes comparing models of early- and late-stage PD. The project includes three specific aims to determine the impact of increasing cGMP and cAMP levels using specific PDE inhibitors and comparing animal models of different disease stages. Studies include analysis of motor behavior, cellular activity with various electrophysiologic techniques, and parameters of molecular changes in the brain, such as the expression of PDEs. In specific aim 1, we will use rodent (rat) models and focus on behavioral analysis after selection of appropriate pharmacological tools for manipulating nucleotide levels with high specificity. In specific aim 2, we will use the same models to analyze the drug impact on SPN function using transgenic rats for cell resolution. In specific aim 3, we will examine the effects of PDE inhibitors in primate models assessing both behavioral and physiological outcomes. In addition, we will analyze the striatal PDE expression changes developed in the late-stage PD. Our approach includes the use of innovative animal models, pharmacological analysis, modern technologies (optogenetics), multiple RNA in situ hybridization analysis, and a combination of rodent and primate studies to generate refined data with translational application. These studies will shed light on the mechanisms underlying deficient and altered SPN responses to DA. Furthermore, we expect to identify molecular targets for developing new therapeutic strategies that can improve the life quality of patients with PD.