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; Manfredsson, Fredric P; Benskey, Matthew J et al. (2016) Impact of age and vector construct on striatal and nigral transgene expression. Mol Ther Methods Clin Dev 3:16082
Kneynsberg, Andrew; Collier, Timothy J; Manfredsson, Fredric P et al. (2016) Quantitative and semi-quantitative measurements of axonal degeneration in tissue and primary neuron cultures. J Neurosci Methods 266:32-41
Paumier, Katrina L; Luk, Kelvin C; Manfredsson, Fredric P et al. (2015) Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis 82:185-99
Nordström, Ulrika; Beauvais, Geneviève; Ghosh, Anamitra et al. (2015) Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease. Neurobiol Dis 73:70-82
Collier, Timothy J; O'Malley, Jennifer; Rademacher, David J et al. (2015) Interrogating the aged striatum: robust survival of grafted dopamine neurons in aging rats produces inferior behavioral recovery and evidence of impaired integration. Neurobiol Dis 77:191-203
Grabinski, Tessa M; Kneynsberg, Andrew; Manfredsson, Fredric P et al. (2015) A method for combining RNAscope in situ hybridization with immunohistochemistry in thick free-floating brain sections and primary neuronal cultures. PLoS One 10:e0120120
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
Kanaan, Nicholas M; Collier, Timothy J; Cole-Strauss, Allyson et al. (2015) The longitudinal transcriptomic response of the substantia nigra to intrastriatal 6-hydroxydopamine reveals significant upregulation of regeneration-associated genes. PLoS One 10:e0127768
Fischer, D Luke; Collier, Timothy J; Cole-Strauss, Allyson et al. (2015) High-Frequency Stimulation of the Rat Entopeduncular Nucleus Does Not Provide Functional or Morphological Neuroprotection from 6-Hydroxydopamine. PLoS One 10:e0133957
Madhavan, Lalitha; Daley, Brian F; Davidson, Beverly L et al. (2015) Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration. PLoS One 10:e0137136

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