 |
 |
|
|
||
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
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 Parkinson’s disease and DYT1 dystonia. 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.
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. We have expanded our Parkinson’s related research work to encompass other recently discovered disease genes, as indicated by the areas of interest listed below.
Current areas of interest include: 1) Biology of the PARK8 protein LRRK2; 2) the relationship between proteasome dysfunction and neuronal degeneration; 3) the mechanism underlying the MPTP resistance of synuclein null mice.
DYT1 dystonia DYT1 dystonia is an intriguing neurological disorder that is characterized by prolonged involuntary twisting movements. Interestingly, DYT1 dystonia is a disorder of neuronal signaling rather than neurodegeneration, and is thought to result from abnormal basal ganglia function. In addition, it is a neurodevelopmental disease, manifesting during a discrete “vulnerable period” during early childhood. 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 produces a dramatic re-localization of torsinA from the endoplasmic reticulum to the nuclear envelope, 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. Specifically, we have identified lamina-associated polypeptide 1 (LAP1) as a torsinA-interacting protein at the nuclear envelope, and have found that torsinA null or homozygous disease knock in mice both exhibit early postnatal lethality and severely altered nuclear membranes.
Current areas of interest include: 1) The use of cell-based and drosophila screens to identify additional molecules in the torsinA pathway; 2) further characterizing the interactions between torsinA, LAP1 and LULL1 (another torsinA-interacting molecule); 3) behavioral and neurobiological characterization of the disease model heterozygous DYT1 knock in mice. |
