Aging and Parkinson's disease: Models of therapeutics and neurologic comorbidity. This is an A2 application for a Udall Parkinson's Disease Center of Excellence from the University of Cincinnati directed by Timothy J. Collier, Ph.D. Two less studied aspects of Parkinson's disease (PD) are the neural mechanisms associated with development of adverse consequences of disease and treatment (such as depression and therapy-induced dyskinesias) and mechanisms associated with translational therapeutics (such as subthalamic nucleus DBS and progenitor ceU 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 proposal consists of four projects and two cores that interconnect and serve the projects. Project 1 examines the roles of maladaptive changes in spine morphology in suboptimal recovery provided by grafted dopamine (DA) neurons and the development of therapy-induced dyskinesias. Project 2 will determine the degree and mechanism of neuroprotection for the DA system conferred by high frequency electrical stimulation of the subthalamic nucleus. In particular, stimulation effects on neurotrophic mechanisms wUl be examined. Project 3 tests the hypothesis that preservation of the structure and function of the injured nigrostriatal system following engraftment of undifferentiated neural progenitor ceUs is not a product of replacement of DA neurons by grafted cells, but is mediated by graft-induced protection and/or regeneration of mature host DA neurons. The goal of Project 4 is to gain insight into the co-mingling of PD, stress, anxiety and depression. It will test the hypothesis that comorbid depression exacerbates the behavioral deficits, neurochemical abnormalities, and neurodegeneration associated with PD via deleterious glucocorticoid mechanisms. AH projects will utilize well-established rat models and examine differences and similarities of mechanisms and outcomes in the context of advancing chronological age. To the extent that plasticity is characteristic of PD, it provides points of access to harness its therapeutic effects and curtail its negative effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
3P50NS058830-05S1
Application #
8792679
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Sieber, Beth-Anne
Project Start
2009-09-30
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$2,500
Indirect Cost
Name
Michigan State University
Department
None
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Polinski, Nicole K; Gombash, Sara E; Manfredsson, Fredric P et al. (2015) Recombinant adenoassociated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain. Neurobiol Aging 36:1110-20
Gombash, S E; Manfredsson, F P; Mandel, R J et al. (2014) Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways. Gene Ther 21:682-93
Hemmerle, A M; Dickerson, J W; Herman, J P et al. (2014) Stress exacerbates experimental Parkinson's disease. Mol Psychiatry 19:638-40
Levine, Nathan D; Rademacher, David J; Collier, Timothy J et al. (2013) Advances in thin tissue Golgi-Cox impregnation: fast, reliable methods for multi-assay analyses in rodent and non-human primate brain. J Neurosci Methods 213:214-27
Madhavan, Lalitha; Daley, Brian F; Sortwell, Caryl E et al. (2012) Endogenous neural precursors influence grafted neural stem cells and contribute to neuroprotection in the parkinsonian rat. Eur J Neurosci 35:883-95
Hemmerle, Ann M; Herman, James P; Seroogy, Kim B (2012) Stress, depression and Parkinson's disease. Exp Neurol 233:79-86
Gombash, Sara E; Lipton, Jack W; Collier, Timothy J et al. (2012) Striatal pleiotrophin overexpression provides functional and morphological neuroprotection in the 6-hydroxydopamine model. Mol Ther 20:544-54
Spieles-Engemann, Anne L; Steece-Collier, Kathy; Behbehani, Michael M et al. (2011) Subthalamic nucleus stimulation increases brain derived neurotrophic factor in the nigrostriatal system and primary motor cortex. J Parkinsons Dis 1:123-36
Kordower, Jeffrey H; Dodiya, Hemraj B; Kordower, Adam M et al. (2011) Transfer of host-derived * synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis 43:552-7
Soderstrom, Katherine E; O'Malley, Jennifer A; Levine, Nathan D et al. (2010) Impact of dendritic spine preservation in medium spiny neurons on dopamine graft efficacy and the expression of dyskinesias in parkinsonian rats. Eur J Neurosci 31:478-90

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