Study Rationale:
Being the primary component of Lewy bodies -- protein clumps that are the pathological hallmark of Parkinson's disease (PD) -- the protein alpha-synuclein plays the central role in PD. The production and spread of alpha-synuclein in a healthy brain is a natural process, but in disease, this same process can harm the brain by spreading toxic alpha-synuclein from one region to another. In this study, we aim to identify critical components of the process of alpha-synuclein release from the cell. We ultimately aim to prevent alpha-synuclein buildup outside of brain cells while preserving the small amount of the protein necessary for normal brain functioning.
Hypothesis:
We previously showed that spontaneous flow of calcium into the cell through specialized channels -- gates on the surface of the cell that open and close as needed -- is necessary for the release of alpha-synuclein. We hypothesize that calcium channels regulate the release of alpha-synuclein from brain cells.
Study Design:
We will use specific toxins, such as those present in venoms of spiders and snails, to prevent opening and closing of each of the five types of calcium channels. We will then measure the amount of alpha-synuclein released from nerve cells in the presence of these toxins. This will allow us to determine the channel types that are involved in alpha-synuclein release. Since the channels are made of proteins, we will determine what proteins these are and where in the brain of pre-clinical models they are located. Finally, we will screen commercially available drugs that can disable calcium channels to see whether any of these drugs reduce the release of alpha-synuclein.
Impact on Diagnosis/Treatment of Parkinson's disease:
In this study, we aim to identify a molecule that regulates the release of alpha-synuclein from the cell and a drug that disables this molecule. Since drugs that disable calcium channels -- calcium channel blockers -- have been used for the treatment of hypertension and neurological disorders, we hope to repurpose at least one of the available drugs for slowing PD progression.
Next Steps for Development:
If we identify a type of calcium channel that can be disabled with drugs, we will first determine where these channels are located in the human brain using brain tissue donated by people after death. Also, it will be critical to study possible side effects of disabling calcium channels because these channels play an important role in the brain, heart and muscle functions.