Study Rationale: In Parkinson’s disease (PD), alpha-synuclein forms abnormal clumps in nerve cells, causing their death. By the time people develop PD, these alpha-synuclein aggregates have spread across many brain regions. Nerve cells remove unwanted proteins by different mechanisms, including destroying them inside the cell or releasing them to the cell exterior in extracellular vesicles. A tiny fraction of nerve cell-derived extracellular vesicles (NEV) enter the circulation and are detectable in blood. By studying individuals who have — or at high risk of developing — PD, we have discovered that nerve cells secret alpha-synuclein in extracellular vesicles years before the onset of motor symptoms.
Hypothesis: We hypothesize that release of alpha-synuclein in extracellular vesicles can be measured to identify people at risk of developing PD or to monitor disease progression.
Study Design: Using our assay, we will isolate NEV from serum and measure alpha-synuclein in samples collected from people with or at risk of developing PD. We will investigate whether the amount of NEV alpha-synuclein in these individuals at baseline, or the rate at which it changes with time, identifies those that go on to develop PD or other biological markers of the disease. We will also assess whether changes in NEV alpha-synuclein levels with time correlate with disease severity. Lastly, we will further optimize the assay for use in the clinic and potentially to quantify less abundant pathological forms of alpha-synuclein.
Impact on Diagnosis/Treatment of Parkinson’s disease: A blood-based test is urgently needed to identify those individuals most likely to benefit from therapies that aim to stop or slow PD progression and to objectively monitor response to such therapies.
Next Steps for Development: We will work with industry, regulators and other stakeholders to develop a diagnostic kit and to test individuals who have already entered clinical trials.