Straightening the Mis-Folded Proteins of Alpha-Synuclein
Alpha-synuclein if the protein molecule that is found in Lewy bodies and is one culprit that is thought to be responsible for the symptoms of PARKINSON’S DISEASE. Scientists have been working hard to understand how alpha-synuclein infiltrates the cells and neurons and exactly what its role is in human biology. It is known that alpha synuclein is at the root of many of the problems of neurodegenerative diseases, but how to remove or suppress this protein has proven extremely elusive and resistant to the best of scientific techniques.
Dr. James Shorter, an associate professor of Biochemistry and Biophysics from the Perelman School of Medicine at the University of Pennsylvania may have discovered a unique and interesting approach that could help solve the alpha synuclein dilemma. His research looked at yeast proteins, and he discovered a specific yeast protein Hsp104 that is able to dissolve mis-folded proteins of alpha-synuclein in the plasma of cells.
Unfortunately, it is not so simple and straightforward. Hsp104 is one of the better known proteins on our planet; however, it does not exist in humans or animals. Dr. Shorter says “We don’t understand why animals have lost the gene for Hsp104, but at the same time, we’ve been wondering: ‘Is there a therapeutic opportunity in this?’” His research has shown that although Hsp104 is effective, it is not perfectly effective and increasing the effectiveness of this protein is the new direction in his research.
His lab has been re-engineering variants of Hsp104. Finding the right variant that can suppress the mis-folded alpha synuclein while also improving the function of the cell is the challenge. While any number of variants might to the job, they might also do more than prevent the clumping of alpha-synuclein and therein would lie some serious problems. So it is no easy task to engineer this particular protein to become an accurate therapeutic product with a focused target. It is also a protein that is foreign to animal and humans, so side effects or toxicity are also important considerations.
His research up until now has been with yeast models, and has been successful. The next step was to test it in a more sophisticated, multi-cellular model, for which a primitive worm model was chosen. This work was a collaboration with Dr. Guy Caldwell from the University of Alabama. And it was successful. The next challenge is to move to even more complex animal models, such as mice.
Although this research is still in some very early stages, it is exciting that a foreign molecule can be engineered to obtain therapeutic benefit and holds the promise that perhaps eventually it will become an important agent for ameliorating the symptoms or possibly eliminating the cause of those symptoms in PARKINSON’S DISEASE and other neurodegenerative diseases.
Jackrel, M.E., M.E. DeSantis, B.A. Martinez, L.M. Castellano, R.M. Stewart, K.A. Caldwell, G.A. Caldwell, and J. Shorter^. (2014). Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell. 156:170–182
Review by Marcia McCall