Alpha-Galactosidase A as a Therapeutic Target for Parkinsonís Disease
Target Validation, 2014
Objective/Rationale: † † † † † ††
Alpha Galactosidase A (alpha-Gal A) is an enzyme that recycles lipids in cells. Our preliminary data demonstrates alpha-Gal A deficiency in brains of Parkinsonís disease patients is associated with the accumulation of alpha-synuclein, a protein that promotes the onset and progression of Parkinsonís disease. The goal of our project is to determine if increasing alpha-Gal A in a model of Parkinsonís disease confirms its potential as a therapeutic target.†
For this project we will use an alpha-synuclein over-expressing model. We will genetically over-express alpha-Gal A in the substantia nigra, a brain region that degenerates in Parkinsonís disease. We will determine if increasing alpha-Gal A in the brain reduces the alpha-synuclein-associated pathology that occurs in these models. We will measure alpha-synuclein aggregates by biochemical and histochemical techniques.
Relevance to Diagnosis/Treatment of Parkinsonís Disease: † † † † † † † † † ††
Drugs that increase alpha-Gal A are already in use for treating Fabry disease, a rare lysosomal storage disorder. If alpha-Gal A is found to be decreased in Parkinsonís disease brain, this would suggest a novel drug target and drugs that are already approved for clinical use may be ďrepurposedĒ for treating Parkinsonís disease. Such treatments may actually delay progression of Parkinsonís disease rather than just treat the symptoms as only current therapies can offer.
Anticipated Outcome: † † † † †
If our hypothesis is correct, we will observe a decrease in these pathological alpha-synuclein aggregates in the brains of over-expressing models that have been subjected to increased expression of alpha-Gal A. This would justify the need for further experiments to assess the ability of alpha-Gal A to protect neurons in models of Parkinsonís disease, and would justify studies of existing alpha-Gal A therapeutics for their usefulness in treating Parkinsonís disease.
Although the main function of the alpha Galactosidase A (alpha-Gal A) enzyme is to help the cell process lipids, it is also known to affect the level of alpha-synuclein, the sticky protein that clumps in the brains of people with Parkinsonís disease (PD). The overall goal of this project was to determine if excessive production -- over-expression -- of alpha-Gal A reduces the accumulation of alpha-synuclein in the brains of pre-clinical models with Parkinsonís features. First, we designed a method of increasing alpha-Gal A production in the brain of the models and then confirmed its over-expression in the substantia nigra, the brain region that contains dopamine-producing nerve cells. Once we confirmed that the method works, we launched a large-scale study, in which pre-clinical models were made to over-express either alpha-Gal A or a control protein that has no effect on the brain. Unfortunately, our studies revealed that over-expression of both the control protein and alpha-Gal A caused untoward, moderate to severe loss of dopamine-producing nerve cells in the substantia nigra. This finding precludes any further studies of alpha-synuclein in the brain of pre-clinical models over-expressing alpha-Gal A and suggests that the over-expression method itself may kill neural cells. This side effect of the experimental method must be addressed before we continue our investigation.
Assistant Professor in the Department of Pathology, Molecular and Cellular Pathology Division at University of Alabama at Birmingham
Location: Birmingham, Alabama, United States
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