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According to our matching algorithm, John Shacka is the likely recipient of the following grants.
| Years |
Recipients |
Code |
Title / Keywords |
Matching
score |
| 2016 — 2017 |
Shacka, John J |
R21Activity Code Description:
To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Alpha-Galactosidase a: a Novel Target For Reducing Alpha-Synuclein Toxicity @ University of Alabama At Birmingham
PROJECT SUMMARY The pathological accumulation of alpha-synuclein (?-syn) is believed to play a major role in Parkinson's disease (PD) pathogenesis. The autophagy-lysosome pathway (ALP) provides for the high-capacity clearance of ?-syn and its dysfunction is well-documented in PD. Inhibiting the ALP has been shown to induce ?-syn accumulation. Conversely, excess ?-syn has been shown to inhibit the ALP. Because the lysosome is critical for ?-syn clearance we believe its continued investigation will further delineate mechanisms of PD pathogenesis and foster development of PD therapeutics. Alpha-Galactosidase A (?-Gal A) is a soluble lysosomal enzyme, with mutations causing the rare lysosomal disorder Fabry disease. While it is unknown if ?- syn accumulates in Fabry patients, our analysis of postmortem PD brains indicates a decrease in ?-Gal A activity specific to specimens with increased ?-syn pathology. Our preliminary data also indicate reduced ?-Gal A activity in neuroblastoma cells following the conditional over-expression of ?-syn. Together with our report of ?-syn pathology and altered ALP markers in ?-Gal A-deficient mouse brain, these findings suggest a strong link between ?-Gal A deficiency and ?-syn accumulation. However, whether ?-Gal A deficiency exacerbates the neurotoxic potential of ?-syn is unknown. Increasing ?-Gal A activity via enzyme replacement therapy (ERT) is clinically approved therapy for Fabry disease. Because ERT has limited CNS bioavailability, there is a critical gap in understanding its potential for treating PD. To help bridge this gap we developed novel research tools to increase ?-Gal A activity in neuronal systems, including its dose-responsive increase in neuronal cells via ERT, and transgenic mice that exhibit two-fold increases in ?-Gal A brain activity. Our preliminary data in neuroblastoma cells shows that ?-Gal A ERT enhances the clearance of over-expressed ?-syn. However, whether increasing ?-Gal A activity attenuates ?-syn-associated neurotoxicity has not been tested. Taken together, we hypothesize that ?-syn-associated neurotoxicity is exacerbated by ?-Gal A deficiency and is attenuated by increasing ?-Gal A activity. In Aim 1 we will determine if ?-Gal A-deficiency in primary neuron cultures exacerbates neurotoxicity resulting from the exogenous addition of ?-syn pre-formed fibrils (PFFs) in a manner concomitant with ALP disruption. We will also determine if ?-Gal A?deficient mice exhibit exacerbated loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra following AAV2-mediated over- expression of human wild-type ?-syn. In Aim 2 we will determine if ?-syn PFF-mediated neurotoxicity in primary neuron cultures is attenuated by ?-Gal A ERT or the transgenic over-expression of ?-Gal A and if this protection is regulated by the ALP. We will also determine if ?-Gal A over-expressing mice exhibit a reduction in TH-positive neuron loss resulting from AAV2-?-syn. If our hypothesis is correct, it would suggest that ?-Gal A deficiency regulates ?-syn pathogenesis, a mechanism worthy of future investigation, and would accelerate the development of therapeutics for PD that act by increasing CNS ?-Gal A activity.
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