Study Rationale
Alpha-synuclein aggregates called Lewy bodies are the hallmark of Parkinson’s disease (PD). Methods to measure alpha-synuclein in cerebrospinal fluid do exist today. However, these methods cannot clearly identify Parkinson’s patients, most likely because they do not measure the exact form(s) of alpha-synuclein that create Lewy bodies, but rather “total” alpha-synuclein. Alzheimer’s disease research suffered a similar challenge when initial assays for “total” amyloid-beta (the Alzheimer’s corollary to alpha-synuclein) showed no value as a biomarker test, but assays for a subspecies of the protein changed testing capabilities.
Hypothesis:
We hypothesize that it will be possible to find and quantify Lewy body-specific forms of alpha-synuclein in brain tissue. If such forms are identified, we will develop and validate ultra-sensitive assays that specifically quantify the species for use as markers of Lewy body pathology.
Study Design:
We will use a combination of biochemical fractionation, antibody-based purification and highly specific analytical methods (e.g., mass spectrometry and liquid chromatography) to study which forms of alpha-synuclein are present in brain tissue with and without Lewy bodies. We will then develop methods to measure the amount of the alpha-synuclein species that look most promising.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
A tool to measure the Parkinson’s-specific form/forms of alpha-synuclein could be useful tools to diagnose PD and other synuclein diseases such as dementia with Lewy bodies, to examine the pathophysiology of these disorders directly in patients, and to identify and monitor treatment effects.
Next Steps for Development:
If we find alpha-synuclein species that reflect the PD disease process, we will try to develop methods to quantify them and set up a patient study.