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Funded Studies

Gaining Mechanistic Insights into PINK1 Genetic Variants

Study Rationale: Mutations in the Parkin and PINK1 genes cause early-onset familial Parkinson's disease (PD). These genes produce enzymes that function together to degrade damaged mitochondria, the powerhouse of the cell. Healthy mitochondria are required for the long-term survival of neurons, and mitochondrial damage is associated with PD. PINK1 acts as a “fire alarm” by building up on damaged mitochondria and tagging them for degradation by Parkin. However, we still have a poor understanding of how genetic mutations in PINK1 render the protein malfunctional. Our goal is therefore to study the impact of PD-associated mutations on the normal function of PINK1. 

Hypothesis: We hypothesize that PD-linked mutations will impair the ability of PINK1 to “build up” in response to mitochondrial damage and to subsequently activate Parkin. We will therefore seek strategies to stimulate PINK1, which could reverse the effects of disease-causing mutations.  

Study Design: We have established a series of to characterize the various steps involved in the activation of PINK1 in response to damage. We have selected 42 mutations that we will test using our models of PINK1 function. These experiments will enable us to better classify these mutations and determine how they cause a loss of PINK1 function. Then we will assess whether specific modifications in PINK1 can stimulate its function and determine whether these modifications can rescue disease-causing mutations. In parallel, we will also test whether these mutations can be rescued by potential drugs that are targeted at PINK1. 

Impact on Diagnosis/Treatment of Parkinson’s disease: Providing a systematic and thorough assessment of Parkinson-causing mutations in PINK1 will help define how individuals carrying these mutations should be treated, because we will know exactly what biochemical pathway is affected. The work will also provide us with proof-of-concept data that PINK1 stimulation can rescue disease-causing mutations.  

Next Steps for Development: The next step will be to determine whether stimulating PINK1 in a human neuron model or animal model, can rescue disease-causing mutations. These preclinical experiments will be critical to determine how carriers of certain PINK1 mutations can be treated most effectively. 


  • Jean-François Trempe, PhD

    Montreal, Quebec Canada

  • Edward A. Fon, MD

    Montreal QC Canada

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