At the 2016 World Parkinson Congress (WPC 2016) in Portland Oregon, I introduced alpha-synuclein as “The Big Kahuna.” It is the protein for which we found the first PD-causing gene mutation in a large family from Contursi, Italy, a small village southeast of Naples. That was 20 years ago, and alpha-synuclein continues to be the dominant player in understanding the disease process.
We’ve known for a while that PD pathology progresses as alpha-synuclein spreads from cell to cell. Recently, a team of researchers from Johns Hopkins University School of Medicine published a landmark paper in Science identifying the role of the lymphocyte-activation gene (LAG3) protein in perpetuating that spread of alpha-synuclein between cells. LAG3 binds to the pathological alpha-synuclein and facilitates its entry into neighboring cells. PD mice engineered to lack LAG3 had delayed loss of critical dopamine neurons as well as delay of behavioral difficulties. LAG3 reduction of PD pathology thus provides a new therapeutic target to slow the progression of Parkinson’s.
The good news is that LAG3 inhibitors are already being used in the burgeoning field of cancer immunotherapy. Cancer cells hijack the body’s natural defense by inhibiting activation of the very cells that attack it. LAG3 is one of a class of “immune checkpoint inhibitors” that do this by blocking cell-to-cell interaction. Using antibodies against LAG3 has thus proven promising for treating various cancers and if, it proves effective in delaying PD in humans, might be fast-tracked for approval.
At Thursday’s Wrap up session of (WPC 2016) an audience member expressed confusion over whether alpha-synuclein was a gene or a protein. “Both,” I answered using the analogy of an old fashion tissue dress pattern. If you make even a tiny change in that dress pattern, the final dress will reflect that change. Both the pattern and the final product can be called “dress.” Similarly, mutations, or changes in a gene affect the resultant protein and both the gene and the protein are referred to as “alpha-synuclein.”