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Funded Studies

Autophagy and Mitochondrial Dysfunction as Potential Therapeutic Targets in Inherited Parkinson's Disease

Study Rationale:
Mutations (changes) in the gene that controls the production of enzyme glucocerebrosidase (GCase) are the most common risk factor for inherited Parkinson's disease (PD). We have recently shown that dysfunction of GCase causes dysfunction of mitochondria (powerhouses of the cell), which, in turn, has been known to be associated with Parkinson's. Not only do GCase mutations cause mitochondrial dysfunction, but they also disrupt autophagy, the process of removal of dysfunctional mitochondria from the cell. This leads dysfunctional mitochondria to build up inside the cell. We aim to determine whether compounds that activate autophagy can restore mitochondrial function and, therefore, improve cells' health. We also aim to determine whether autophagy represents a therapeutic target in people with PD.

We hypothesize that activation of autophagy may restore the function of mitochondria in people carrying PD-linked GCase mutations.

Study Design:
We have generated stem cells from skin samples donated by people with PD-linked GCase mutations. We then converted these stem cells into dopamine-producing nerve cells. We will use these to test the ability of various pharmaceutical compounds to promote autophagy. We will then select the most effective compounds and establish whether these improve mitochondrial function using a sophisticated, powerful microscope.

Impact on Diagnosis/Treatment of Parkinson's Disease:
Several inherited forms of Parkinson's are caused by mutations associated with mitochondrial dysfunction that affect mitochondrial autophagy. Establishing whether mitochondrial dysfunction is reversible and whether it can be influenced by pharmaceutical compounds is key in determining whether mitochondrial autophagy is a viable therapeutic target.

Next Steps for Development:
Pharmaceutical compounds that can promote autophagy are already used in clinics for purposes other than Parkinson's, and, therefore, much is already known about their safety and efficacy. Direct demonstration of improvement in mitochondrial function and autophagy would provide strong basis for moving such compounds into clinical trials for Parkinson's disease.


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

    London United Kingdom

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