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
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.