Motor Neuron Center
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Room 310
Tel 212.342.0444
Email: wtd3@columbia.edu
RESEARCH THEME: The Molecular and Cellular Mechanisms of Motor System Disease

The Molecular and The central goal of our studies is to unravel the molecular and cellular mechanisms of diseases that disrupt the motor system. Our primary focus is on DYT1 dystonia and Parkinson's disease. For each of these projects, we focus our efforts on disease genes that cause these disorders, employing a range of molecular, cellular, and whole animal studies to dissect the normal role of disease proteins, and how pathogenic mutations lead to disease.

DYT1 dystonia

DYT1 dystonia is an intriguing neurodevelopmental disorder that is characterized by prolonged involuntary twisting movements. Although the protein mutated in DYT1 dystonia is expressed in all tissues, the disease manifests as a selective motor disorder. Thus, understanding the pathogenesis of this illness may provide unique insights into motor system development and function.

We have pursued a variety of experimental approaches to begin to understand this disease. DYT1 dystonia is caused by a dominant mutation (deletion of a single amino acid) in torsinA, a protein of unknown function that resides within the endoplasmic reticular/nuclear envelope lumen. We discovered that the dystonia-causing torsinA mutation alters the interaction of torsinA with its binding partners, and have made a number of observations that indicate that decreased torsinA function at the nuclear envelope is likely to be a key factor in disease pathogenesis. Studies in genetically modified mice demonstrate that loss of torsinA function leads to striking morphological changes of nuclear membrane of a number of neuronal classes, including motor neurons (see illustration at sidebar). Current studies are aimed at understanding the molecular mechanisms of torsinA function and dysfunction.

Parkinson's Disease

Parkinson's disease is the second commonest age-related neurodegenerative disease after Alzheimer's disease and is characterized by progressive degeneration of midbrain dopaminergic neurons. Our Parkinson's disease-related initially centered upon the biology of alpha-synuclein, a protein that is concentrated in presynaptic nerve terminals in close association with synaptic vesicles. We generated alpha synuclein null mice and demonstrated that they are strikingly resistant to the Parkinsonian neurotoxin MPTP. Our Parkinson's disease work is currently focused on the biology of the PARK8 protein leucine rich repeat kinase 2 (LRRK2). Mutations in this protein are a relatively common cause of genetically defined Parkinson's disease. In addition, LRRK2 mutations have also been implicated in the motor neuron degenerative disease ALS.

EDUCATION AND TRAINING:

1986 B.S. Duke University
1990 M.D. Washington University School of Medicine
1990-1992 Postdoctoral Fellowship with Dr. Steve Hyman, MGH Boston
1993-1997 Clincal Training in Neurology and Movement Disorders, Columbia U.
1997-2001 Postodoctoral Training with Dr. Rene Hen, Columbia University

HONORS AND AWARDS:

1988 Howard Hughes Medical Institute Postdoctoral Fellowship for Physicians
2001 Merrill Young Investigator Award and Laboratory Research Award
2002 Young Investigator Scholarship, Pediatric Neurotransmitter Disease Association
2005 The Harold and Golden Lamport Award for Excellence in Clinical Science Research


SELECTED PUBLICATIONS:

  • Goodchild RE, Kim CE, Dauer WT. Loss of the Dystonia-Associated Protein TorsinA Selectively Disrupts the Neuronal Nuclear Envelope. Neuron. 2005 48:923-32.
  • Dauer W, Kholodilov N, Vila M, Trillat A-C, Goodchild R, Larsen K, Staal R, Tieu K, Schmitz Y, Yuan A, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R. Resistance of a-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci U S A. 2002 99:14524-12549.
  • Dauer W, Przedborski S. Parkinson’s Disease: Mechanisms and Models. Neuron 2003 39:889-909.
  • Goodchild RE, Dauer W. Mislocalization to the nuclear envelope: an effect of the dystonia-causing mutation in torsinA. Proc Natl Acad Sci U S A. 2004 101:847-852.
  • Goodchild RE, Dauer WT. The AAA+ protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein. JCB, 2005; 168: 855-862.

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