STIMULATING BETA-GLUCOCEREBROSIDASE (GCASE) ACTIVITIES PREVENT ALPHA-SYNUCLEIN AGGREGATION IN PARKINSON’S DISEASE
Author and Affiliation: Adebisi Benjamin Temidayo; Osun State University, Nigeria
Presenter and Affiliation: Adebisi Benjamin Temidayo; Osun State University, Nigeria
Aim: to prevent the accumulation of alpha-synuclein, which is the protein implicated in Parkinson’s disease, by the stimulation of beta-glucocerebrosidase, a lysosomal enzymes that is vital in degradation of cellular debris and misfolded proteins.
Background: Beta-Glucocerebrosidase (GCase), a lysosomal enzyme that has glucosylceramidase activity in ceramide metabolism, plays a major role in the pathogenesis of Gaucher’s disease and also, responsible for a reasonable percentage in the etiopathogenesis of Parkinsion’s disease (PD). GBA1 mutations, however, result in decreased GCase activities eliciting decrease proteasomal degradation of aggregates of alpha synuclein, which is the underlying mechanisms in PD pathogenesis.
There has, also, being a reciprocal link between GCase activities and alpha-synuclein accumulation/aggregation; meaning, decrease in GCase activities will increase alpha-synuclein accumulation and an increase in GCase activities invariably reduce the alpha-synuclein aggregation.
Alpha-synuclein accumulation has being linked to loss of nigrostrial dopaminergic neurons; this is due to the fact that overexpression of alpha-synuclein results in its oligomerization and eventual Lewy body formation, which is found mostly in PD patients
Methods: The experimental approach involves cellular delivery of small interferon RNA (SiRNA) into the brain of mice to deliver the loss of function particles into the neuron. The RNA is further processed and forms the single strand SiRNA which will suppress the expression of the GBA1 gene. Upon suppression, the structural conformer and oligomers of alpha synuclein will be monitored in the biofluid. Then, SimPull assay will be performed on the alpha synuclein oligomers in both the mutant mice and the mutant mice treated with the pharmacological remedy.
Results: Ambroxol, the pharmacological remedy, consists of small molecules chaperone which are competitive inhibitors of GCase, the molecules may bind to the misfolded GCase correctly folding it preventing its accumulation and bringing the lysosomes into its optimal proteasomal degradation of alpha synuclein aggregate
Conclusion: The chaperonic effect of ambroxol and ability to correctly fold mutant Gcase will increase lysosomal action which, invariably, stimulate degradation of alpha synuclein, hence prevent Parkinson’s disease.