Study Rationale: The formation of toxic protein aggregates is an early step in the pathology of several neurodegenerative disorders, including Parkinson’s disease (PD). Using computer simulations, we discovered that these toxic aggregates contain an unusual structure that we dubbed an alpha-sheet. We have since demonstrated that this structure is found in the toxic aggregates of more than a dozen different amyloid proteins, including the alpha-synuclein that accumulates in Parkinson’s disease (PD). This unusual structure represents an attractive target for the early detection of disease and the development of potentially disease-modifying therapeutics.
Hypothesis: We hypothesize that detection of toxic alpha-synuclein aggregates in cerebrospinal fluid and plasma can provide a means to diagnose PD and a window into its earliest stages of disease.
Study Design: We will adapt the assay we developed for identifying toxic aggregates of amyloid-beta in Alzheimer’s disease to facilitate detection of alpha-synuclein. Our preliminary results are very encouraging and here we will expand our screening to look for alpha-synuclein in plasma samples.
Impact on Diagnosis/Treatment of Parkinson’s disease: PD is particularly difficult to diagnose in its earliest stages. Because accumulation of toxic oligomers is a molecular pathology that begins in the earliest stages of the disease, their detection should enable earlier diagnosis.
Next Steps for Development: With proof of concept and validation in a large number of diverse samples, our assay could be employed in clinical trials and made available to people with PD through the Clinical Laboratory Improvement Amendments (CLIA) program while seeking FDA approval.