Identifying and Localizing Toxic Oligomeric A-Syn with Morphology Specific Nanobodies

Objective/Rationale: 
Aggregation and deposition of the protein, a-synuclein (a-syn), has been strongly correlated with PD and other related neurodegenerative disorders. The a-syn protein occurs in a variety of forms and complexes all of which can aggregate into different morphologies including various toxic oligomeric species. Here we will utilize morphology specific antibody based reagents to identify which specific oligomeric a-syn species can distinguish between CSF samples taken from PD and healthy patients.

Project Description: 
Our approach is to use highly selective morphology specific antibody reagents (nanobodies) to detect the presence of different aggregated a-syn species in post-mortem CSF samples taken from PD, Alzheimer’s (AD) and healthy donors. We have developed nanobodies that selectively recognize different aggregated a-syn morphologies and others that recognize toxic aggregated beta-amyloid species implicated in neurodegenerative diseases such as Alzheimer’s. We will use a panel of these highly selective nanobodies in conjunction with a very sensitive electronic biosensor that can detect trace amounts of a target directly from complex human samples such as CSF. We will test different PD, AD and healthy CSF samples to determine which specific aggregated protein species can best distinguish between healthy, PD and AD samples.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
We have developed reagents that specifically recognize different aggregated species of a-syn, and here will identify which a-syn species represent promising diagnostic targets. A-syn can form various small aggregated species that are toxic to cells and can serve as early indicators of disease progression. Identification of aggregated a-syn species present in CSF that distinguish PD from other neurodegenerative diseases and healthy brains would provide valuable biomarkers to facilitate early diagnosis of PD and to assess effectiveness of different therapeutic treatments.

Anticipated Outcome: 
We expect to identify which aggregated species of a-syn represent promising diagnostic targets for distinguishing PD from other neurodegenerative diseases and from healthy brains. Detection and quantification of these selected aggregated forms of a-syn and beta-amyloid in CSF samples will facilitate diagnosis of PD and other related neurodegenerative diseases. Detection of selected toxic a-syn forms in CSF can provide effective biomarkers for early detection of PD and to monitor the effectiveness of therapeutic interventions.