Novel Mitochondrial Biomarkers in Genetically Stratified Parkinson's Disease Patients

Study Rationale:
Parkinson's disease has many causes and can be thought of as an umbrella term for patients with a diverse set of experiences. Research suggest that dysfunction of mitochondria (e.g., the energy powerhouses of our cells) contributes to the development of Parkinson's disease. But this dysfunction is likely a major cause of the disease in only a specific group of patients with genetic mutations affecting mitochondria. In this study, we aim to identify a mitochondrial signature (i.e., biomarker) in people with specific genetic mutations and in a group of patients with idiopathic (i.e., cause unknown) Parkinson's who have prominent mitochondrial dysfunction. Establishing and validating this biomarker is the aim of the present study.

Hypothesis:
We hypothesize that a mitochondrial signature in different groups of Parkinson's patients will help identify patients who have a higher degree of mitochondrial dysfunction.

Study Design:
We will establish and validate the biomarker of mitochondrial dysfunction in two different ways. First, we will assess the ability of mitochondria to produce energy by measuring the mitochondrial membrane potential in patient blood cells using a technique called fluorescence-activated cell sorting. Second, we will closely monitor metabolic turnover in the Cori cycle. The Cori cycle refers to the metabolic pathway in which lactate (produced in the muscles) moves to the liver where it is converted to glucose (sugar), which then returns to the muscles and is metabolized back to lactate. To follow this pathway that is indicative of mitochondrial function, we will use a special method called dried blood spot (DBS)/gas chromatography/mass spectrometry (GC/MS). Both types of biomarkers will be obtained in patients that are stratified according to their degree of mitochondrial dysfunction.

Impact on Diagnosis/Treatment of Parkinson's disease:
Identifying patients with a high degree of mitochondrial dysfunction could inform clinical trial design as well as patient selection for clinical trials of drugs designed to enhance mitochondrial function.

Next Steps for Development:
Next steps will be to further validate the mitochondrial biomarker in independent patient cohorts and to use it for selection of patients for clinical trials testing drugs that specifically target mitochondrial function.