|
|
William T. Dauer, M.D.
Assistant Professor of Neurology and Pharmacology
|
Research
Summary
We are interested in understanding the fundamental molecular and cellular mechanisms of diseases that disrupt normal motor control, with a specific focus on those that disturb basal ganglia function. Our main focus is on exploring the pathogenesis of Parkinson's disease and DYT1 dystonia.
Our Parkinson's disease-related work centers upon the biology of alpha-synuclein, a protein that is concentrated in presynaptic nerve terminals in close association with synaptic vesicles, and appears to play a role in the rate of vesicular cycling. Mutations in alpha synuclein cause a form of dominantly inherited Parkinson's disease. We have generated alpha synuclein null mice and demonstrated that they are strikingly resistant to the Parkinsonian neurotoxin MPTP. This basis for this resistance to cell death is likely to provide insight into the normal function of synuclein, and thus far appears to relate to an alteration in synaptic vesicle function. Current studies are focused on further exploring the mechanism underlying this resistance to cell death. Our studies in neurodegeneration also include projects that employ genetic strategies to 1) explore the relationship between proteasome dysfunction and neurodegeneration, 2) testing the reversibility of neurodegeneration in genetic mouse models and 3) to identify unique properties of dopaminergic neurons.
Primary dystonia is a disease characterized by prolonged involuntary twisting movements, reflecting abnormal motor system function. To explore this class of motor disorders we study the molecular and cellular mechanisms that produce DYT1 dystonia, a dominantly inherited childhood-onset form of primary dystonia. This disease is caused by a dominant mutation (deletion of a single amino acid) in torsinA, a ER lumenal protein of unknown function. We have found that the dystonia-causing torsinA mutation produces a dramatic re-localization of torsinA from the endoplasmic reticulum to the nuclear envelope in both patient tissue and neurons from transgenic mice. In addition, we find that disease-associated torsinA recruits wild type protein to the nuclear envelope, providing a molecular mechanism to explain the dominant inheritance of the disease. Our studies also suggest that the nuclear envelope recruitment results from an abnormal interaction of the mutant protein with a normal nuclear envelope substrate of torsinA. We are extending these cellular studies to guide the characterization of torsinA knock in, knock out and transgenic mice. These mouse models are also being used to study the factors responsible for the reduced penetrance and variable expressivity of the DYT1 mutation.
http://www.sklad.cumc.columbia.edu/neuroscienceinitiatives/index.php?page=28&bio=40
|
Selected Publications:
1. Kholodilov N, Olga Yarygina O, Oo, T, Zhang H, Sulzer D, Dauer W, Burke RE. (2004) Regulation of the development of mesencephalic dopaminergic systems by the selective expression of glial cell line-derived neurotrophic factor in their targets. J. Neurosci.
24(12):3136-46.
2. Goodchild RE, Dauer W. (2004) Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. Proc Natl Acad Sci USA.
101:847-52.
3. Rideout HJ, Dietrich P, Savalle M, Dauer W, Stefanis L. (2003) Regulation of alpha-synuclein by bFGF in cultured ventral midbrain dopaminergic neurons. J Neurochem.
84(4):803-13.
4. Dauer W, Przedborski S. (2003) Parkinson's disease: mechanisms and models. Neuron.
39:889-909.
5. Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R. (2002) Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA.
99:14524-9.
6. Yamamoto A, Hen R, Dauer W. (2001) The ons and offs of inducible transgenic technology: a review. Neurobiol Dis.
8(6):923-32.
|
|
|
|
|
|
|
top
|
