Research Progress: Understanding Alpha-Synuclein

Every cell in the body carries a copy of the entire genome, but only uses those portions of it that it needs. Each gene is like a recipe for a corresponding protein, (which are molecular machines) each with a specialised function within the cell such as transport within the cell. The study of gene expression alone is insufficient for understanding a disease. The proteins that result from gene expression are just as important and often pose a more complex problem for scientists looking to unravel what is going wrong in Parkinson's.

Some rare forms of PD can be considered truly 'genetic'. They can be inherited from a parent and caused by a mutation in a gene that either makes a particular protein incorrectly or just in much higher quantities than the cell actually needs. Some proteins responsible for inducing genetic PD are known. Most cases of PD are not genetic in this sense, this is referred to as 'idiopathic' Parkinson's, but that does not mean that genetics are not involved in the disease, but they may increase our susceptibility to PD.

A projection from one brain cell to another that is blocked up with deposits of alpha– synuclein.

Now we are using the gene chip data to study proteins that appear to behave abnormally in PD brains. Alpha-synuclein is one protein that we are particularly interested in. In brains affected by PD, proteins that are not broken down properly clump together inside brain cells. Some of these clumps, called inclusions, can grow so large that they fill the cell body and cause it to burst. Other inclusions occur in the thin processes by which brain cells communicate with each other, preventing messages from being transmitted from one brain region to another. It is known that alpha-synuclein is a major component of these inclusions, but no one knows what this protein’s function is in the cell or what might cause it to dysfunction and accumulate in this manner. There are many possibilities. The protein-regulated mechanisms that are responsible for making or breaking down alpha-synuclein might be at fault, or there might be a problem with proteins that are supposed to work with alpha-synuclein in accomplishing its job in the cell. Of course, finding out just what that job is in the first place is a high priority for us and many other researchers around the world. We are trying to learn more about alpha-synuclein and how it interacts with other proteins by using a technique called immunohistochemistry, in which a coloured probe is attached to the protein of interest, allowing us to observe its location and make inferences into its function. Another technique, in situ hybridisation, will allow us to visualise which cells are actively making these proteins from their genetic code. Again we are relying on tissue from the PDS Tissue Bank to carry out all these experiments. We hope to gain an understanding of how and why these proteins begin to malfunction so that we can develop new approaches to treat PD.