Fetal cell transplantation strategies have targeted the striatum to reestablish dopaminergic (DA) function within the basal ganglia.. Our preliminary data indicate that the DA reinnervation of other targets within the system produce significant behavioral changes, when established as single targets, and may be necessary in combination to maximize functional recovery in Parkinson's disease (PD). To test this hypothesis, we will first determine the effects of dopamine reinnervation of substantia nigra, in addition to the striatum, in a MPTP primate model of PD. In addition, the subthalamic nucleus is a major component of the indirect pathways and motor circuitry of the basal ganglia. Our preliminary studies of dopamine reinnervation of the STN as a single target have shown significant behavioral recoveries in models of PD. We will therefore explore the contribution of DA reinnervation of the STN in behavioral and functional recovery of MPTP-induced parkinsonism. We will transplant DA cells to subthalamic nucleus alone or in combination with placement in striatum and substantia nigra. The evaluation of functional effects in all of our experiments will be determined by PET and MRI studies, including 11C-CFT, dopamine D2 receptors with 11C-raclopride, pharmacological MRI studies of amphetamine and apomorphine stimulated changes in striatal blood volume. Studies of neurochemical include N-acetyl aspartate (NAA), creatine (Cr) and choline (Cho). Behavioral Actigraph movement activity and video analysis completes the functional analysis. The functional data will be analyzed and intercorrelated. This project will determine how DA neural replacement in all of the regions denervated in PD will improve and fully restore the dysfunctional circuitry responsible for PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
1P50NS039793-01
Application #
6230095
Study Section
Special Emphasis Panel (ZNS1-SRB-K (01))
Project Start
1999-09-30
Project End
2004-07-31
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Mc Lean Hospital (Belmont, MA)
Department
Type
DUNS #
City
Belmont
State
MA
Country
United States
Zip Code
02478
Wang, Xin; Li, Nuomin; Xiong, Nian et al. (2017) Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson's Disease. Mol Neurobiol 54:2878-2888
Xiong, Nian; Li, Nuomin; Martin, Eden et al. (2016) hVMAT2: A Target of Individualized Medication for Parkinson's Disease. Neurotherapeutics 13:623-34
Hallett, Penelope J; Deleidi, Michela; Astradsson, Arnar et al. (2015) Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease. Cell Stem Cell 16:269-74
Hallett, Penelope J; Cooper, Oliver; Sadi, Damaso et al. (2014) Long-term health of dopaminergic neuron transplants in Parkinson's disease patients. Cell Rep 7:1755-61
Lindvall, Olle; Barker, Roger A; Brüstle, Oliver et al. (2012) Clinical translation of stem cells in neurodegenerative disorders. Cell Stem Cell 10:151-5
Cooper, Oliver; Hallett, Penny; Isacson, Ole (2012) Using stem cells and iPS cells to discover new treatments for Parkinson's disease. Parkinsonism Relat Disord 18 Suppl 1:S14-6
Hallett, Penelope J; McLean, Jesse R; Kartunen, Andrew et al. (2012) ýý-Synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits. Neurobiol Dis 47:258-67
McLean, Jesse R; Hallett, Penelope J; Cooper, Oliver et al. (2012) Transcript expression levels of full-length alpha-synuclein and its three alternatively spliced variants in Parkinson's disease brain regions and in a transgenic mouse model of alpha-synuclein overexpression. Mol Cell Neurosci 49:230-9
Deleidi, Michela; Isacson, Ole (2012) Viral and inflammatory triggers of neurodegenerative diseases. Sci Transl Med 4:121ps3
Deleidi, Michela; Cooper, Oliver; Hargus, Gunnar et al. (2011) Oct4-induced reprogramming is required for adult brain neural stem cell differentiation into midbrain dopaminergic neurons. PLoS One 6:e19926

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