The protein alpha-synuclein (a-syn) has been conclusively linked to Parkinson’s disease. The prevailing theory today states that a-syn is a causative agent in the development of the disease. Consequently, removal of a-syn has been proposed as a therapeutic avenue in the treatment of PD. However, we have previously shown that loss of a-syn in mature neurons result in cell-death. The objective of this project is to further characterize the cascade of pathological events that ensue following loss of a-syn in anatomically distinct neuronal populations.
In this proposal we will utilize viral vectors do deliver short hairpin RNAs (genetic elements designed to abolish the production of a protein) targeting a-syn to a pre-clinical brain. We will target two distinct populations of cells, the substantia nigra (group of cells that die in PD) and the cerebellum (not affected in PD) in order to determine whether toxicity associated with loss of this protein is specific to cells affected in PD. In addition, we will delineate the exact time-course of pathological events following the loss of the protein as well as determining what level of a-syn is required for neuronal survival. In addition, we will investigate the ability of neurons to store the neurotransmitter dopamine following loss of a-syn, as mishandling of dopamine may lead to cellular toxicity.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Before a-syn can be viewed as a potential therapeutic target in PD the exact effects resulting from the loss of this protein in adults have to be carefully studied. If the outcome of this study confirms that a-syn is absolutely required for the survival of neurons then such a therapeutic approach would no longer be considered safe. On the contrary, this study would provide a foundation on which future research into the relevance of a-syn in disease can progress.
Upon successful completion of this project we expect to have defined an exact time-line of pathological events following the loss of a-syn. This will in turn facilitate future research into the exact molecular events that is the result of a-syn knockdown. In addition, we expect to have determined whether loss of a-syn results in mishandling of dopamine. Mishandling of dopamine may lead to the formation of reactive oxygen species, a biochemical process that has been documented to confer toxic effects.