Promising Outcomes of Original Grant:
The protein alpha-synuclein (a-syn) has been strongly correlated with PD, and small a-syn aggregates are very toxic and may be an early indicator of the disease. We have developed ligands that can specifically recognize different aggregate forms of a-syn. These reagents can be labeled for use as SPECT imaging ligands to determine where and when different a-syn aggregates occur in PD animal models. We showed that these radiolabeled ligands do recognize recognize aggregated a-syn in PD brain tissue of a pre-clinical model and therefore have potential value as SPECT ligands for studying PD.
Objectives for Supplemental Investigation:
In the first part of this project we verified that we can radiolabel our morphology specific ligands and maintain binding activity. The next step is to demonstrate that the ligands can cross the blood brain barrier following intravenous injection. We will genetically add several different peptide sequences that have been shown to facilitate transfer into the brain to the a-syn ligand, and determine which construct most efficiently crosses the blood brain barrier.
Importance of This Research for the Development of a New PD Therapy:
Aggregation of a-syn into small toxic structures is a key early step in the progression of PD. Developing ligands that can detect when and where these toxic structures occur can provide an early diagnostic test for PD as well as providing the a means to therapeutically target and remove the toxic aggregates.