UCL Queen Square Institute of Neurology


Targeting glucocerebrosidase for disease-modifying treatments in Parkinson’s disease

 Mutations of the glucocerebrosidase (GBA) gene represent the most important risk factor for

Parkinson’s disease (PD): 7-10% of PD patients have GBA mutations, and GBA mutations increase

the risk for PD 20 to 30-fold. The GBA pathway intersects with recognised PD pathogenetic

processes, including lysosomal and mitochondrial dysfunction, and mitophagy defects such as related

to PINK1 mutations. In post-mortem brain, cell and animal models of GBA mutations, there is

evidence of an inverse relationship between glucocerebrosidase enzyme (GCase) activity and alphasynuclein

(SNCA) concentrations.

We are investigating the interaction of GBA mutations with SNCA and PINK1 and the hypothesis that

restoring or increasing GCase activity results in a reduction of SNCA levels and reversal of PD

biochemical and pathological features.

Novel mechanistic pathways/interactions relevant to PD will be investigated and performed in parallel

with a proof-of-principle therapeutic study of small molecule chaperones to increase lysosomal

GCase. In vitro and in vivo studies will be performed in parallel by the CoEN sites using state-of-the-art

models including SNCA expression cell lines and transgenic mice, PINK1 mutant mice, AAV-GBA

mutation transfection and PD patient cell lines with GBA mutations.

Results will be the basis for further exploration of GCase target validity in PD.