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.