Morphology Specific Anti-Synuclein Nanobodies as Therapeutics for PD
Alpha-Synuclein Therapeutics, 2010
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 determine which specific oligomeric a-syn species represents the best therapeutictarget in a pre-clinical model of PD.
Our approach is to target and neutralize toxic a-syn aggregates in a pre-clinical model of PD using morphology specific single chain variable domain antibody fragments (or nanobodies). While a-syn is an intrinsically unstructured protein, it can adopt folded forms that facilitate formation of toxic aggregated species. Here we will express three different nanobodies, each of which recognizes a different a-syn morphology, in a transgenic pre-clinical model of PD to determine which a-syn aggregate species represents the best therapeutic target. We will utilize two different variants of each nanobody, one designed to target extracellular a-syn and one designed to also target intracellular a-syn for a total of six different therapeutic studies. Each nanobody targets a specific form of a-syn inhibiting further aggregation and reducing toxicity by blocking potential harmful interactions with cells.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Aggregation of a-syn into toxic species has been strongly linked to the progression of PD. We have developed reagents that specifically recognize different aggregated species of a-syn, and here will identify which a-syn species represent good therapeutic targets. These therapeutic reagents are designed to target only toxic aggregated forms of a-syn and not beneficial monomeric forms. The reagents can also be used to identify the presence of specific a-syn species as an early indicator of PD.
We expect to identify which aggregated species of a-syn represent promising therapeutic targets for treating PD. We will determine whether targeting only extracellular aggregated a-syn or both intracellular and extracellular a-syn aggregates provides better protection against neurodegeneration in a pre-clinical model of PD. These studies will help to not only identify suitable therapeutic targets for PD but provide reagents that very selectively react with these targets.
Professor, Chemical Engineering Department at Arizona State University