Authors:
Emily D. Haley1-4
Tonia E.Tse1Hailin Lu5
John J. Shacka, PhD1
Departments
1. Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA
2. School of Medicine, Nephrology Division, University of Alabama at Birmingham, Birmingham, AL, USA
3. Undergraduate Neuroscience Program, University of Alabama at Birmingham, Birmingham, AL, USA
4. Science and Technology Honors Program, University of Alabama at Birmingham, Birmingham, AL, USA
5. School of Medicine, Infectious Diseases Division, University of Alabama at Birmingham, Birmingham, AL, USA
Abstract
Parkinson Disease (PD), the second most common neurodegenerative disease,affects 1% of Americans over the age of 65. PD pathology is characterized by dopaminergic neuron loss and accumulation of insoluble alpha-synuclein (αsyn) aggregates. Pre-clinical studies suggest that the aberrant accumulation αsyn contributes to PD pathogenesis. The autophagy lysosomal pathway (ALP) is a metabolism pathway capable of high capacity clearance of αsyn. Thus targeting the clearance of αsyn, in particular by enhancing ALP function, could be a valuable treatment option for PD. We have shown previously that brains of mice deficient in the lysosomal enzyme alpha-Galactosidase A (αGalA) exhibit the pathological accumulation of αsyn concomitant with ALP dysfunction. These findings led us to hypothesize that increasing αGalA activity would enhance αsyn clearance. To test this hypothesis, we examined if increasing αGalA activity using recombinant αGalA (Fabrazyme, Genzyme Corp.) accelerates the clearance of conditionally over-expressed αsyn in M17 human neuroblastoma cells. Fabrazyme treatment increased the level and activity of αGalA in M17 cells and promoted the clearance of over-expressed αsyn. These data suggest the utility of αGalA activity as a therapeutic target for promoting the clearance of αsyn in a preclinical model of PD.