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Funded Studies

Targeting the Lysosomal Pathway to Ease Mitochondrial Dysfunction in IPSC-Derived Neurons from People with Parkinson's and GBA Mutations

Study Rationale:
Mutations of the GBA gene, which encodes the enzyme glucocerebrosidase (GCase), are associated with Parkinson's, and we have recently shown that loss of GCase activity gives rise to impaired mitochondrial function, itself associated with Parkinson's. We propose that impaired clearance of damaged mitochondria by a process called autophagy (which is dysfunctional in people with GBA mutations), allows the accumulation of dysfunctional mitochondria. We now ask whether compounds that increase autophagy activity are able to restore mitochondrial function and therefore improve cell health in people with Parkinson's disease (PD).

We propose that increasing autophagy activity may restore mitochondrial function in cells of people carrying PD-related GBA mutations.

Study Design:
We will generate stem cells from skin fibroblasts (connective tissue cell) obtained from people carrying PD-related GBA mutations and differentiate these to generate dopaminergic neurons as our model system. We will establish the ability of a number of compounds to promote autophagy in these cells using standard biochemical assays (laboratory tests). We will then select the most effective compounds and establish whether these improve mitochondrial function using a high-content, high-throughput fluorescence microscopy system.

Impact on Diagnosis/Treatment of Parkinson's Disease:
Parkinson's is associated with mitochondrial and autophagy dysfunction. Establishing whether mitochondrial dysfunction is reversible and whether it can be driven pharmacologically is key in establishing these pathways as viable therapeutic targets.

Next Steps for Development:
A number of compounds that stimulate autophagy are already in clinical use for other purposes, so clinical benchmarks are already established. Demonstrating improvement in cellular biochemistry would provide strong basis to move such compounds into clinical trials.

Final Outcome

In our ongoing work, we have been focusing on generating stem cells from skin samples donated by people with Parkinson's disease (PD) associated with mutations (changes) in the gene for enzyme glucocerebrosidase (GBA). From these stem cells, we created dopamine-producing nerve cells, which will be used as a model of GBA-associated Parkinson's. We also worked with several types of cells to be able to compare different PD-related GBA mutations. The cell types we created will serve as a very valuable resource for drug testing and for studying basic disease mechanisms.

We demonstrated that pre-clinical models lacking GBA have dysfunctional mitochondria and compromised energy supply in nerve cells. We then explored whether subtle GBA mutations also have an impact on mitochondrial function. We also aimed to determine whether mitochondrial function is useful in assessing the action of candidate drugs. Our data to date suggests that the GBA mutations alter mitochondrial function significantly. In the future, we will explore the underlying mechanisms that link GBA mutations with mitochondrial dysfunction to identify pathways that can be developed as novel therapeutic targets for GBA-related Parkinson's disease.

February 2018


  • Michael R. Duchen, BA (Oxon), MBBS, FRC

    London United Kingdom

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