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 #
3P50NS038370-15S1
Application #
8932500
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
2015-07-31
Budget Start
2013-08-01
Budget End
2015-07-31
Support Year
15
Fiscal Year
2014
Total Cost
$160,000
Indirect Cost
$60,000
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Mosharov, Eugene V; Borgkvist, Anders; Sulzer, David (2015) Presynaptic effects of levodopa and their possible role in dyskinesia. Mov Disord 30:45-53
Robeson, William; Dhawan, Vijay; Ma, Yilong et al. (2014) Radiation absorbed dose to the basal ganglia from dopamine transporter radioligand 18F-FPCIT. Biomed Res Int 2014:498072
Morimoto, Richard I; Cuervo, Ana Maria (2014) Proteostasis and the aging proteome in health and disease. J Gerontol A Biol Sci Med Sci 69 Suppl 1:S33-8
Foster, Daniel J; Gentry, Patrick R; Lizardi-Ortiz, Jose E et al. (2014) M5 receptor activation produces opposing physiological outcomes in dopamine neurons depending on the receptor's location. J Neurosci 34:3253-62
Fedorowicz, Maja A; de Vries-Schneider, Rosa L A; Rub, Cornelia et al. (2014) Cytosolic cleaved PINK1 represses Parkin translocation to mitochondria and mitophagy. EMBO Rep 15:86-93
Cebrián, Carolina; Zucca, Fabio A; Mauri, Pierluigi et al. (2014) MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun 5:3633
Janicki, S C; Park, N; Cheng, R et al. (2014) Estrogen receptor ? variants affect age at onset of Alzheimer's disease in a multiethnic female cohort. Dement Geriatr Cogn Disord 38:200-13
Bras, Jose; Guerreiro, Rita; Darwent, Lee et al. (2014) Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet 23:6139-46
Romaní-Aumedes, J; Canal, M; Martín-Flores, N et al. (2014) Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease. Cell Death Dis 5:e1364
Guardia-Laguarta, Cristina; Area-Gomez, Estela; Rüb, Cornelia et al. (2014) ?-Synuclein is localized to mitochondria-associated ER membranes. J Neurosci 34:249-59

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