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

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Director: Timothy J. Collier, Ph.D.

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


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.

Central Theme and Center Structure

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 promote neuroprotection of the nigrostriatal system; (3) examination of the interactions of grafted undifferentiated neural progenitor cells (NPCs) and NPCs endogenous to the host brain that protect and repair the nigrostriatal system; and (4) 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 is the incorporation of advancing chronological age as a variable of interest as it influences the expression of comorbid conditions and outcomes derived from therapeutic interventions.

The Udall Center assembles four principal investigators as Project and Core Leaders to provide a team-based approach to our studies: Timothy Collier, Ph.D, Jack Lipton, Ph.D., Caryl Sortwell, Ph.D., and Kathy Steece-Collier, Ph.D. 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 Research Advances

The focus of the Udall Center at Michigan State University is to better understand the neural mechanisms associated with development of adverse consequences of disease and treatment, and to identify mechanisms associated with translational therapeutics. One theme of our Center is that understanding the gene expression changes associated with DA neuron degeneration, the benefits of current therapeutics, and their adverse consequences, will lead to the identification of novel targets for therapeutic intervention. To this end, gene array studies were performed on tissue samples from the nigrostriatal system of rats over numerous time points during the degeneration of DA neurons. A number of genes showed significant increases during active DA neuron degeneration following neurotoxin exposure (6-hydroxydopamine, 6-OHDA). Among them was the small proline-rich repeat 1a (Sprr1a) gene, which is a member of the regeneration associated gene (RAG) family. These genes have been shown previously to be upregulated in the periphery in response to injury where they are thought to play a central role in axonal regeneration. A role for Sprr1a in the CNS had not previously been considered. Nigral tissue undergoing DA neuron degeneration displayed a significant 10-fold increase in Sprr1a that was confirmed using quantitative PCR. Currently, experiments in cultured neurons and in vivo will determine whether Sprr1a can provide axonal and neuronal protection from degeneration in models of PD.

In a second set of studies we examined gene expression changes associated with one adverse consequence of PD therapy: levodopa-induced dyskinesias (LIDs). We have found that in a subpopulation of parkinsonian rats that develop this medication-induced side-effect, a specific gene that regulates thyrotropin releasing hormone (TRH) is dramatically increased approximately 30-fold. TRH was the first hypothalamic hormone discovered and is classically known to be involved in thyroid endocrine function, but its role in basal ganglia function and dysfunction remains unclear. We have confirmed that TRH is increased in a subpopulation of neurons in the striatum and in substantia nigra pars reticulata, not as a consequence of levodopa treatment but in association with LIDs specifically. As a next step, we will manipulate the genetic machinery of brain cells to over-produce or silence the TRH gene in those cells where the elevation occurs. Such studies will allow us to determine whether TRH plays a critical role in development of this negative side-effect of parkinsonian pharmacotherapy.

Finally, progress in our understanding of causes and treatments for PD require models that more closely approximate the range of pathology and behavioral signs associated with the disease. In collaboration with investigators at the University of Pennsylvania Udall Center, we have adapted their previously characterized mouse model of progressive α-synucleinopathy to a model of rat α synucleinopathy. Our preliminary results show that injection of exogenous pre-formed α-synuclein (α-syn) fibrils (PFFs), a toxic form of α-syn, into rat brain causes the progressive spread of α-syn pathology throughout the brain. Furthermore, our findings are the first to demonstrate that the α-syn seeding approach in rats results in death of DA neurons in the substantia nigra. Further characterization of this model will allow us to use it as a platform to test novel therapies for PD. Establishment of this model in rats allows for a wider array of surgical interventions and functional motor assessments than those possible in mice.

Resources Available

In addition to the rat progressive 6-OHDA toxin model of parkinsonism, we are characterizing two additional preclinical rat models of PD: 1) viral vector-mediated overexpression of human wildtype α-syn (rAAV2/5 α-syn) targeted to the nigrostriatal system, and, 2) injection of preformed α-syn fibrils (PFFs) directly into the striatum. The latter PFF model is being established in collaboration with the University of Pennsylvania Udall Center (Drs. Lee, Trojanowski, and Luk). We continue to provide expertise in cell culture of primary rat DA neurons, rat models of dyskinesias and deep brain stimulation, and viral vector production and characterization.

Select Publications

Aberrant restoration of spines and their synapses in L-DOPA-induced dyskinesia: involvement of corticostriatal but not thalamostriatal synapses.
Zhang Y, Meredith GE, Mendoza-Elias N, Rademacher DJ, Tseng KY, Steece-Collier K. J Neurosci. 2013 Jul 10; 33(28):11655-67. PMID: 23843533

Last updated November 6, 2013