The Morris K. Udall Center of Excellence for Parkinson's Disease Research at Michigan State University, with the University of Cincinnati

Director: Timothy J. Collier, Ph.D.

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

Website: http://translationalscience.msu.edu/Udall.html

Central Theme

The Udall Center at Michigan State University focuses on studies of two aspects of Parkinson’s disease (PD): neural mechanisms associated with development of adverse consequences of disease and treatment, and mechanisms associated with translational therapeutics. 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, our Center 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 Udall Center assembles six principal investigators at two institutions to provide a team-based approach to our studies: Timothy Collier, Ph.D, (Director, Michigan State University), James Herman, Ph.D. (University of Cincinnati), Jack Lipton, Ph.D. (Michigan State University), Kim Seroogy, Ph.D. (University of Cincinnati), Caryl Sortwell, Ph.D. (Michigan State University), and Kathy Steece-Collier, Ph.D. (Michigan State University). The Center includes an Administrative Core to coordinate activities and communications associated with the projects, and an Analytical Chemistry, Gene Expression, and Surgical Core to provide the animal model and analytical endpoints common to all projects.

Recent Significant Advances

• Preservation of striatal dendritic spine density by administration of nimodipine enhances therapeutic efficacy and reduces unwanted side-effects following grafting of immature DA neurons. In addition, recent preliminary findings indicate that delayed nimodipine treatment also is effective in restoring dendritic spine density when administered to DA depleted rats with established deficits in spine number. This provides hope that treatment with calcium channel blockers may remain effective in patients with PD already experiencing re-modeling of the striatum.
  
• Subthalamic nucleus deep brain stimulation (STN-DBS) halts ongoing degeneration of the nigrostriatal system, ameliorates parkinsonian forelimb akinesia, and results in elevation of brain derived neurotrophic factor (BDNF) in the nigrostriatal system and primary motor (M1) cortex.
  
• Neuroprotection of injured DA neurons following implantation of undifferentiated neural progenitor (mNP) cells derived from embryonic rat midbrain likely involves multiple neurotrophic factors produced by these cells: BDNF, NT-3, and pleiotrophin. Similar human-derived NP cells appear to have neuroprotective effects for midbrain DA neurons specific for the region from which they are derived: those derived from midbrain exert protection, those derived from spinal cord do not.
  
• In contrast to the effects of chronic variable stress/depression, corticosterone administration alone is not sufficient to worsen behavioral deficits produced by DA depletion. The data suggest that glucocorticoids per se are not the primary mediators of stress-related exacerbation of motor deficits in this PD model. Taken together with previous findings from other neural systems, it is likely that the effects of stress are either mediated by neural excitation, or that glucocorticoids interact with the effects of neural excitation to promote DA neuron degeneration.

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

• Continue to explore whether normalizing intraspine calcium with nimodipine in severely DA-depleted animals after the initial spine loss has occurred will allow for recovery of spine density. The capacity for spine restoration will be compared in young and aged rats. In addition, we will begin analysis of the ultrastructure of synapse phenotypes and generalized dendrite morphology associated with dyskinetic behavior; dyskinesia indices will be correlated with abnormal spine morphology and/or aberrant synapse formation on MSNs in animals that display these behaviors.
  
• Investigate the mechanism of STN DBS-associated increases in BDNF and determine the relationship of BDNF upregulation to STN DBS-associated neuroprotection. Explore the impact of STN DBS on additional trophic factors.
  
• Explore mechanisms associated with grafted NP cell-induced neuroprotection utilizing analysis of microdissected region of grafted cells and substantia nigra with PCR-based microarrays of neurotrophic factors, cytokines associated with inflammation, and markers of oxidative stress.
  
• Continue to explore the role of glucocorticoids in the stress/depression-induced exaggeration of nigrostriatal dysfunction and degeneration in the 6-OHDA model.

Selected Recent Publications

Spieles-Engemann AL, Behbehani MM, Collier TJ, Wohlgenant SL, Steece-Collier K, Paumier K, Daley BF, Gombash S, Madhavan L, Mandybur GT, Lipton JW, Terpstra BT, Sortwell CE.
"Stimulation of the rat subthalamic nucleus in neuroprotective following significant nigral dopamine neuron loss."
Neurobiol. Dis. 2010 39(1): 105-15 [PMID: 20307668]

Spieles-Engemann AL, Collier TJ, Sortwell CE
"A functionally relevant and long term model of deep brain stimulation of the rat subthalamic nucleus: Advantages and considerations."
Eur. J. Neurosci. 32(7): in press.

Soderstrom KE, O’Malley JA, Levine ND, Sortwell CE, Collier TJ, Steece-Collier K.
"Impact of dendritic spine preservation in medium spiny neurons on dopamine graft efficacy and the expression of dyskinesias in parkinsonian rats."
Featured Article: Eur. J. Neurosci. 2010 31(3):478-90 [PMID: 20105237]

Madhavan L, Collier TJ.
"A synergistic approach for neural repair: cell transplantation and induction of endogenous precursor cell activity."
Neuropharmacology 2010 58(6):835-44 [PMID: 19853620]

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.