There are compelling research opportunities for Parkinson's disease (PD) therapies. While L-dopa provides an initial relief, there is a need for alternative strategies to deal with the continued loss of dopaminergic (DA) neurons, axons and terminals. We have a functional collaborative scientific group centered at McLean Hospital, Harvard Primate Center and Massachusetts General Hospital that can investigate neuroprotective, neuromodulatory and neural transplantation approaches for PD. We will use animal models, including MPTP-treated primates with loss of dopamine cells, synapses and function. This work is synergistically linked in four projects: Project 1. A neurophilin ligand induced prevention of dopaminergic degeneration induced by MPTP in the primate. Two paradigms are tested; a) neuroprotection by a neurophilin ligand to reduce the loss of dopamine terminals and b) a regeneration paradigm with post neurophilin ligand treatment to regenerate remaining DA terminals. Project 2. We will test neuronal replacement by fetal dopamine cells into the striatum, the subthalamic nucleus and the substantia nigra in a primate model of PD. We hypothesize that a full reinnervation with novel dopaminergic fibers in these regions will fully restore the dysfunctional circuitry responsible for PD. Project 3. By generating dopaminergic neurons from blastoma stage stem cells, we can obtain renewable cells to be transplanted for functional tests into animal models of parkinsonism. These stem cell derived dopaminergic neurons will be compared in function to these derived from phenotypically normal embryonic fetal cells. Project 4 is an educational component of the grant, with a major commitment to training new scientists PD. These projects are supported by 2 Cores that further integrate these projects; namely, an Administrative Core that supports the research teams involved, and the Imaging Core involving functional MRI and PET scans and analysis. In summary, we feel this compelling research collaboration on novel realistic approaches to PD treatment is of exceptional value. The allocation of these resources will test major scientific hypotheses in protecting, repairing or replacing the dopaminergic system responsible for the signs of PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS039793-04
Application #
6529525
Study Section
Special Emphasis Panel (ZNS1-SRB-K (01))
Program Officer
Oliver, Eugene J
Project Start
1999-09-30
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
4
Fiscal Year
2002
Total Cost
$1,312,315
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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