Parkinson's disease (PD) is the most common neurodegenerative disorder of the basal ganglia. Although many effective treatments for the motor symptoms of PD exist, their benefits are limited in degree and duration. The greatest challenge posed by this disease is to develop therapies that address the underlying degenerative process. The overriding theme of the Udall Center at Columbia is to address this challenge. Our efforts have two guiding principles. The first is that development of such therapies ultimately depends on a better understanding of mechanisms of disease. The second is that patients cannot wait for a full understanding of this disease to be in hand before efforts are made to translate new knowledge into treatments. Based on these principles, our proposal consists of four Projects that will be integrated according to five current central themes in the pathogenesis of PD. Each of the Projects builds on discoveries in the genetics of PD. Project 1 (Sulzer &Cuervo) will continue their important work on the degradation of a-synuclein. Projects 2 (Dauer) and 3 (Greene) will explore, in collaboration, mechanisms of LRRK2 toxicity. Project 4 (Burke) will utilize a new hl_RRK2(R1441G) BAG transgenic model of PD, in which he has identified a dopaminergic axonopathy, in translational investigations. This model will be available to Projects 2 and 3. Project 1 will also examine relationships between processing of synuclein and two important components of the intracellular milieu of dopamine neurons: cytosolic dopamine and calcium. One of the central themes of our Udall Center has been to examine the role of programmed cell death in pathogenesis. This theme has taken on a new importance due to the work of Dr Dauer in Project 3, demonstrating an interaction of LRRK2 with proteins in the extrinsic cell death pathway. Independent lines of investigation in Projects 3 (Greene) and 4 (Burke) have converged on the importance of the survival signaling kinase Akt in the viability of dopamine neurons. The importance of chaperone-mediated autophagy in degradation of synuclein has been discovered in the current funding period in Project 1, and the role of macroautophagy in the maintenance of axons has emerged in Project 4. To support the emphasis in the current proposal on the translational implications of our work, the Center now includes a Brain Bank Core, a Core for Training in Translational Neuroscience, and a Fibroblast Core for the production of human pluripotent cells. Thus the Udall Center at Columbia is poised to discover new approaches to neuroprotection and restoration, and to move these discoveries to the clinic expeditiously.

Public Health Relevance

Current therapies for PD treat only its symptoms, not its progression. The goal of our research is to use new knowledge about the mechanisms of neurodegeneration to develop therapies that will block progression. We use genetic and neurotoxin models to better understand these mechanisms. We realize that patients cannot wait for us to understand mechanisms completely before we try to develop new therapies. Therefore, we will also go forward with translational research to establish novel pharmacologic and gene therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS038370-13
Application #
8138331
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Sieber, Beth-Anne
Project Start
2000-08-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
13
Fiscal Year
2011
Total Cost
$2,083,418
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Kun-Rodrigues, Celia; Ross, Owen A; Orme, Tatiana et al. (2017) Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies. Neurobiol Aging 49:214.e13-214.e15
Wu, Di; Klaw, Michelle C; Connors, Theresa et al. (2017) Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury. Mol Ther 25:2715-2726
Guerreiro, Rita; Escott-Price, Valentina; Darwent, Lee et al. (2016) Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. Neurobiol Aging 38:214.e7-214.e10
Wu, Di; Klaw, Michelle C; Kholodilov, Nikolai et al. (2016) Expressing Constitutively Active Rheb in Adult Dorsal Root Ganglion Neurons Enhances the Integration of Sensory Axons that Regenerate Across a Chondroitinase-Treated Dorsal Root Entry Zone Following Dorsal Root Crush. Front Mol Neurosci 9:49
Louis, Elan D; Clark, Lorraine; Ottman, Ruth (2016) Familial Aggregation and Co-Aggregation of Essential Tremor and Parkinson's Disease. Neuroepidemiology 46:31-6
Chung, Sun Young; Kishinevsky, Sarah; Mazzulli, Joseph R et al. (2016) Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and ?-Synuclein Accumulation. Stem Cell Reports 7:664-677
Pereira, Daniela B; Schmitz, Yvonne; Mészáros, József et al. (2016) Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum. Nat Neurosci 19:578-86
Tambini, Marc D; Pera, Marta; Kanter, Ellen et al. (2016) ApoE4 upregulates the activity of mitochondria-associated ER membranes. EMBO Rep 17:27-36
Liu, Xinmin; Hernandez, Nora; Kisselev, Sergey et al. (2016) Identification of candidate genes for familial early-onset essential tremor. Eur J Hum Genet 24:1009-15
Mosharov, Eugene V; Borgkvist, Anders; Sulzer, David (2015) Presynaptic effects of levodopa and their possible role in dyskinesia. Mov Disord 30:45-53

Showing the most recent 10 out of 228 publications