The Morris K. Udall Center of Excellence for Parkson's Disease Research at Columbia University

Director: Robert E. Burke, MD

Center Title: Mechanisms of dopamine neuron degeneration

Central Theme and Center Description

The Udall Center at Columbia University has now completed its fifth and final year of its 2004-2009 funding period.  The Center has been competitively renewed for 2009-2014.  In the current funding period the Center has consisted of four Projects which share a single integrating theme: to understand the molecular and cellular mechanisms of dopamine (DA) neuron degeneration.  In Project 1, Dr. Serge Przedborski has examined the role of cyclooxygenase type-2 (COX-2) in the mediation of dopamine neuron degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. In Project 2, Drs. David Sulzer and Ana Maria Cuervo have examined the role of the autophagic/lysosomal pathways in the degradation of proteins implicated in PD, and the influence of alterations in their degradation on cytosolic dopamine homoeostasis. Project 3, directed by Dr. Robert Burke, has explored the role of the kinase signaling cascades and ER stress in programmed cell death of dopamine neurons.  Dr. Lloyd Greene, in Project 4, has further evaluated the functional role of ER stress in mediating programmed cell death, and he has assessed the role of death-related gene families identified in the previous funding period by Serial Analysis of Gene Expression (SAGE).

 

Recent Significant Advances

Mutant hR1441G LRRK2 BAC transgenic mice recapitulate cardinal features of Parkinson's Disease

In collaboration with Drs. CJ Li and F Beal at Weil Cornell Medical College we reported in Nature Neuroscience the creation of a new mouse model of Parkinson’s disease that successfully recapitulates the impairments of movement and the brain degenerative changes that occur in the disease.  The model was created by use of a BAC transgenic approach to achieve expression of mutant hR1441G LRRK2.  Dr. Li and his colleagues observed that the mice expressing the mutant, but not the normal form of the gene, became very slow to move at 9 to 10 months of age.  Remarkably, the mice became able to move normally when treated with levodopa.  Histologic analysis of the brains of the mice revealed degeneration not of dopamine neurons themselves, but of their axons.  Axon pathology was demonstrated not only by immunostaining for tyrosine hydroxylase, but also for abnormal phosphorylation of tau, just as in some of the kindreds expressing mutant LRRK2.  The development of this new model represents a very important step forward, not only because it is induced by a known cause of the human disease, but also because it closely resembles the human condition.

 

Available Resources

The mutant hR1441G LRRK2 BAC transgenic micehave been transferred to and are available from the Jackson Laboratory Induced Mutant Resource Repository:

http://www.jax.org/imr/index.html

 

Plans for the Coming Year

Our successfully renewed Udall Center (2009-2014) will consist 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 alpha-synuclein.  Projects 2 (Dauer) and 3 (Greene) will explore, in collaboration, mechanisms of LRRK2 toxicity.  Project 4 (Burke) will utilize a new hLRRK2(R1441G) BAC 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 (Vonsattel & Clark), a Core for Training in Translational Neuroscience (Burke), and a Fibroblast Core (Przedborski) 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.

 

Select Recent Publications

[Columbia Udall Principal Investigators are in BOLD]

Chen X, Rzhetskaya M, Kareva T, Bland R, During MJ, Tank AW, Kholodilov N, Burke RE. Antiapoptotic and trophic effects of dominant-negative forms of dual leucine zipper kinase in dopamine neurons of the substantia nigra in vivo.  J Neurosci 2008;28:672-680.

LiY, LiuW, OoTF, WangL, TangY, Jackson-LewisV, ZhouC, GeghmanK, BogdanovM, PrzedborskiS, BealMF, BurkeRE, LiC.  Mutant hR1441G LRRK2 BAC transgenic mice recapitulate cardinal features of Parkinson’s Disease.  Nature Neuroscience 2009;12:826-828.

Malagelada C, Ryu EJ, Biswas SC, Jackson-Lewis V, Greene LA. RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation.  J Neurosci 2006;26:9996-10005.

Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo AM. Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy.  J Clin Invest 2008;118:777-788.

 

Public Health Statement

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 disease 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.