"Dancing Protein" May Hold the Mystery to Parkinson's Disease
Associate Professor Ashok Deniz (center), pictured here with Research Associates Allan Ferreon (left) and Yann Gambin
Some of the most devastating neurological disorders may come down to little clusters of misfolded proteins. Scientific hypotheses are zeroing in on these "aggregates" that build up in the brains of Alzheimer's and Parkinson's patients.
Ashok Deniz, an associate professor at The Scripps Research Institute, set out to learn more about the proteins that make up these aggregates. Deniz and his team knew that mutations in the gene that produces the protein alpha-synuclein had been linked to early-onset Parkinson's disease and to Alzheimer's disease, and decided that this protein would be the focus of their efforts.
Most proteins must fold into three-dimensional shapes in order to perform their functions. Alpha-synuclein, though, belongs to a class of proteins that remains functional despite often being unfolded.
To learn more, Deniz and the Scripps Research team decided to study the shape of single proteins using a technique called fluorescence resonance energy transfer (FRET). The technique, which Deniz calls a "molecular ruler," measures light emitted from fluorescent dyes that are attached to amino acids in the protein. The light emissions allowed the researchers to measure molecular distances, and thus determine the protein's shape.
They then coaxed the protein to change shapes by increasing the concentration of a soapy solution that mimics the lipids that the protein binds to in the brain. As the investigators increased the concentration of the lipid-like molecules, alpha-synuclein kept pace, changing shape to bind with the growing blobs of molecules.
"What we are showing here directly is that the shape can actively change," Deniz said. "It starts off in an unfolded state, and as we increase the concentration of the lipid mimics, the protein reacts to what is in effect a different binding partner, even though it is the same small molecule at different concentrations. It switches back and forth into different states."
Such shape-shifting has rarely been so directly observed in proteins like alpha-synuclein, which had previously been known to unfold in isolation.
In addition to affecting the protein's function, the ability of alpha-synuclein to change shapes could play a significant role in the formation of disease-related aggregates.
A key next step for the research team will be to figure out which form of alpha-synuclein may accelerate the formation of aggregates found in the brains of Alzheimer's and Parkinson's patients. What they find should be widely applicable to other proteins in these aggregates.
Fluorescent light and shape-shifting proteins may evoke images of "Saturday Night Fever," but the Scripps Research team's results are far more dazzling off the dance floor. Their contributions will carry forward the study of the most devastating neurological diseases. Your support can help make sure that their research is "Stayin' Alive."