Trafficking Defects in Parkinson’s Disease

Another example of where a protein trafficking defect leads to disease, but perhaps not the disease we were expecting.

Glucocerebrosidase (GBA) is a protein involved in lysosomal lipid metabolism[1].

Gaucher’s disease is caused by mutations in GBA which typically result in mis-folded protein that gets degraded in the ER and therefore fails to reach the lysosome[2]. Such mutations are called “trafficking mutants” and are the most common cause of loss-of-activity from GBA mutation[3]. Enzyme replacement therapy (ERT) has greatly extended the lifespan of Gaucher’s patients by replacing the missing GBA enzyme using a recombinant biological drug, restoring GBA activity in lysosomes[4]. Now that a significant number of elderly Gaucher’s patients exist, an interesting connection began to emerge starting in 2007: Gaucher’s patients are up to 20-times more likely to get Parkinson’s than the general population (note that the GBA enzyme given in ERT does not reach the brain, and so neurons remain untreated). While Gaucher’s is a relatively rare disorder, it has also been known for some time that that GBA heterozygotes (Gaucher’s carriers) also have a substantially increased risk of Parkinson’s [5].

In fact, mutations in GBA have become one of the best genetic markers of PD risk accounting for up to 9% of PD patients[6], and targeting GBA refolding was proposed as a promising Parkinson’s drug target in 2011[7]

Sharp Edge Labs uses its protein trafficking assay technology to screen for compounds that can restore GBA trafficking in the brain.   A useful by-product of this work is the possibility of discovering drugs that could also be used for treating lysosomal storage disorders, like Gauchers, with the added benefit of treating the other CNS manifestations of these diseases.

Having discovered trafficking correctors and activators in our screens Sharp Edge Labs uses stem cell-derived neurons  to validate these compounds, and to drive the optimization of those compounds to develop a clinical candidate with CNS penetrance, safety, and functional rescue of GBA in the brains of GBA-mutant Parkinson’s patients.