The take-home message of this manuscript is that increasing the normal number of copies of alpha-synuclein can cause Parkinson’s disease. This was a novel finding.

The protein alpha-synuclein is produced as a part of a cell’s normal function. However, the alpha-synuclein protein is known to be a major component of a particular protein aggregate found in the brains of Parkinson's disease patients, called a "Lewy body." Lewy bodies are found within dopamine-producing nerve cells in the region of the brain damaged in Parkinson's disease. It is not understood why this protein forms these aggregates, but the fact that it does has implicated the alpha synuclein protein in the molecular processes that lead to Parkinson's disease. We identified a family with a rare inherited form of Parkinson's disease and discovered that the disease was caused because instead of inheriting the normal two copies of the gene which produces alpha-synuclien, the affected family members were inheriting four copies each. We later showed that double the number of alpha-synuclein producing genes resulted in a doubling in the production of protein. This finding showed that simply increasing the production of alpha synuclein is enough to cause Parkinson's disease and suggested that a similar mechanism (i.e., increasing alpha synuclein protein) may be occurring in all Parkinson's patients. Furthermore this suggests that treatments which lower alpha-synuclein protein production or increase the cells’ ability to clear the protein would be a good therapeutic strategy, aimed at the treatment of the disease, not merely the symptoms.

I was working in the field of Alzheimer's disease genetics for around three or four years, but when I moved to the Mayo Clinic in Jacksonville, I became more and more involved with Parkinson's disease research. This seemed like a new and exciting field and it was interesting and satisfying to work on the genetics of a disorder that for so long had been thought of as the typical "non-genetic" disease. When I set up my own lab at the National Institute on Aging, the disease in this family seemed like a particularly interesting problem to work on. I thought that finding the genetic lesion causing disease in this family would be particularly informative. I knew too at least one other group had been looking for some time without success, so I knew it would be an exciting and challenging project to work on.