The Morris K. Udall Center of Excellence for Parkinson’s Disease Research at the University of Cincinnati

Director: Timothy J. Collier, Ph.D.

Title: Aging and Parkinson’s Disease: Models of Therapeutics and Neurologic Comorbidity

Central Theme

Many current Udall Centers are focused on understanding the etiology of PD and developing new therapeutics. We believe two less studied aspects of PD are the neural mechanisms associated with development of adverse consequences of disease and treatment (such as stress, depression and levodopa-induced dyskinesias) and mechanisms associated with translational therapeutics (such as subthalamic nucleus electrical stimulation and progenitor cell transplantation). In addition, it long has been appreciated that advancing age is a primary risk factor for PD, yet aging rarely is incorporated into experimental studies. Thus, the present proposal groups these topics under the rubric of “adaptive and maladaptive plasticity” and examines their expression in the context of advancing chronological age. The proposed studies examine such themes as (1) the roles of altered dendritic morphology in projection neurons of the dopamine (DA) depleted striatum in the expression of therapy-induced dyskinesias; (2) exploration of mechanisms associated with electrical stimulation of the subthalamic nucleus (STN) that may promote neuroprotection of the nigrostriatal system; (3) examination of the hypothesis that grafted undifferentiated neural progenitor cells protect and repair the nigrostriatal system not by replacing lost DA neurons but by stimulating plasticity in the host brain; and (4) begin to study the known association of depression with PD to determine whether stress, chronic anxiety and depression exacerbate neurodegeneration and whether manipulation of these states influences the efficacy of therapeutic interventions. A critical aspect of all of the proposed projects will be to incorporate the recurring factor of advancing chronological age on the expression of mechanisms and outcomes derived from therapeutic interventions.

 

Center Structure

The Center consists of four research projects, an Administrative Core and an Analytical Biochemistry, Gene Expression, and Surgical Core. The research projects and project leaders are as follows: Project 1: Profiles of Maladaptive Plasticity: Impact on Graft & Levodopa Efficacy (Kathy Steece-Collier, Ph.D.); Project 2: Subthalamic Nucleus (STN) Deep Brain Stimulation and Neuroprotection (Caryl E. Sortwell, Ph.D.); Project 3: Induction of Dopamine System Plasticity by Grafted Undifferentiated Progenitor Cells (Timothy J. Collier, Ph.D.); Project 4: Glucocorticoid Mechanisms of Stress-Induced Depression and Parkinsonian Symptomology (Kim B. Seroogy, Ph.D. and James P. Herman, Ph.D.).

Center investigators operate as a team; together we have expertise in most techniques ranging from the level of mRNA to animal behavior. This combination of individuals with specific expertise allows our approach to research to be based in problem solving, not based on excellence of execution of an individual technique. Core B (Jack W. Lipton, Ph.D.) serves the science in very tangible ways, providing a nexus both for standardization of the animal model and molecular/biochemical endpoints across projects, and the cross fertilization of findings that will shape the directions of the program for the future. All analytical methods related to determination of the quantity and localization of mRNA, proteins, neurotransmitters and metabolites will be centralized in Core B, providing a consistent analytical link between all projects. All projects benefit from the same team of surgeons performing surgery to produce dopamine-depleting lesions and implant cells, electrodes, and mini-pumps. In particular, the common source of lesion surgery will provide a consistent, standardized parkinsonian animal model as a background to the evaluation of all subsequent experimental interventions specific to each project. This provides an additional link between the individual projects of the Center and enhances the opportunity for direct comparison of outcome measures. The functions of providing cohesive experimental start and end points, as well as the mining and combining of gene expression data from each project to generate consensus targets for study, provides the mechanism that expands the value of each project and plots the course of the program into the future.

 

Recent Significant Advances

Preliminary results from our ongoing studies that formed the basis of our proposal demonstrate that:

• Preservation of the integrity of dendritic spines on striatal medium spiny neurons via nimodipine treatment in severely DA-depleted rats enhances the therapeutic efficacy of fetal DA neuron grafts and reduces the expression of dyskinesias in levodopa-treated animals (Project 1: Profiles of Maladaptive Plasticity: Impact on Graft & Levodopa Efficacy; Project Leader: Kathy Steece-Collier, Ph.D.).
• Initiation of high frequency electrical stimulation of the STN two weeks after initiation of our progressive 6-hydroxydopamine (6OHDA) rat model of PD completely halts progression of nigral DA neuron degeneration (Project 2: Subthalamic Nucleus (STN) Deep Brain Stimulation and Neuroprotection; Project Leader: Caryl E. Sortwell, Ph.D.).
• Implantation of undifferentiated neural progenitor (NP) cells derived from embryonic rat midbrain adjacent to the mature substantia nigra provides partial preservation of nigral neurons following intrastriatal injection of 6OHDA. There is no evidence that NP cells differentiate into replacement DA neurons, and in vitro findings suggest that neurotrophic mechanisms participate, at least in part, in the observed neuroprotection (Project 3: Induction of Dopamine System Plasticity by Grafted Undifferentiated Progenitor Cells; Project Leader: Timothy J. Collier, Ph.D.
• Induction of chronic variable stress, a rat model of depression, coincident with ongoing degeneration of the nigrostriatal DA system produced by 6OHDA exaggerates DA neuron loss and corresponding behavioral deficits (Project 4: Glucocorticoid Mechanisms of Stress-Induced Depression and Parkinsonian Symptomology; Project Leaders: Kim B. Seroogy, Ph.D. and James P. Herman, Ph.D.).

 

Available Resources

Model Systems: cell culture, progressive nigrostriatal degeneration rat model, rat model of DBS, rat model of depression (chronic variable stress), rat model of levodopa-induced dyskinesias.

 

Plans for the Coming Year

Project 1: Conduct a detailed analysis of the impact of striatal dendritic spine integrity on outcome measures following grafting of embryonic DA neurons, including behavioral effects, grafted cell number, graft-derived reinnervation, and levels of DA and metabolites.

Project 2: Continue with the analysis of neuroprotective effects of STN stimulation, comparing high frequency stimulation, low frequency stimulation, and no stimulation on measures of nigral DA neuron number, innervation of striatum, levels of DA and metabolites, and behavior.

Project 3: Conduct a time course study of the phenotypic fate of grafted undifferentiated midbrain neural progenitor cells as they participate in neuroprotection of the DA system.

Project 4: Begin to assess whether glucocorticoid signaling is necessary and sufficient for the stress/depression-induced exaggeration of nigrostriatal degeneration in the 6OHDA rat model.

 

Selected Recent Publications

Steece-Collier K., Soderstrom K, Collier T.J., Sortwell C.E., and Lad E. (2009) “Impact of levodopa priming on dopamine neuron transplant efficacy and induction of involuntary movements in parkinsonian rats.” J. Comp. Neurol., 515:15-30.

Madhavan L., Daley B.F., Paumier K.L., and Collier T.J. (2009) “Transplantation of subventricular zone neural precursors induces an endogenous precursor cell response in a rat model of Parkinson’s disease.” J. Comp. Neurol., 515:102-115.

 

Public Health Statement

Two aspects of Parkinson’s disease (PD) that have received relatively little study are the nervous system mechanisms associated with development of adverse consequences of disease and treatment (stress, depression and medication-induced side-effects) and mechanisms associated with experimental therapies (deep brain stimulation, cell transplantation). In addition, it long has been appreciated that advancing age is a primary risk factor for PD, yet aging rarely is incorporated into experimental studies. Our Center studies these adaptive and maladaptive changes associated with PD and its’ treatments in model systems that incorporate the factor of advancing chronological age.

Our findings suggest that many negative side-effects of disease and treatment can be avoided or improved, and that experimental therapies currently in development may possess previously unrecognized additional benefits. Our goal is that through continued study of these issues our work can provide for development of optimal therapeutics for PD, inform their use in the clinical setting, and ultimately improve the quality of life for those living with PD.