"[This] is an opportunity to test potential disease-modifying therapies."
Kateri Spinelli, Ph.D.
A small protein called alpha-synuclein (α-synuclein) has long been viewed as a potential culprit in the development of Parkinson’s disease (PD). As the protein clumps in brain cells, it seems to have a toxic effect on the brain. Researchers have long asked, how? And why?
The answers are hard to find — in part because we cannot see inside a live brain to observe how α-synuclein moves, and where it goes. But Kateri Spinelli, Ph.D., of Oregon Health & Science University in Portland, OR, a researcher funded by the Parkinson’s Disease Foundation (PDF), has found a way around this challenge — to watch α-synuclein in real-time.
Using a cutting-edge technology that exists in only a few laboratories in the world, Dr. Spinelli uses a glass “window” to see inside the brains of mice. She peeks in and watches α-synuclein, which has been treated with a fluorescent dye to make it easy to see in the brain.
Working with mentor Vivek Unni, M.D., Ph.D., one item that Dr. Spinelli immediately noticed was the presence of a molecular tag attached to α-synuclein clumps in the mouse brain. The tag was composed of molecules called phosphates, which are attached to α-synuclein through a process called phosphorylation (phosphorylation occurs with various proteins in the body as part of normal cellular function).
She wondered: are these extra molecules helping or hurting α-synuclein? So she observed the mouse brains in a number of different circumstances.
First, she prevented most of the phosphates in the mouse brains from attaching to α-synuclein, which led to far fewer extra molecules on the protein. When she observed changes in the brain, the α-synuclein remained largely unchanged — that is, it formed some small clumps, but not the large clumps typically seen in PD. Next, she looked at mice with genetic mutations that prevented their α-synuclein from being tagged with phosphates. This led to these mice also having fewer extra molecules on α-synuclein. Here, the protein was even healthier and clumped less than what she normally saw in PD mice.
Combined with her other work, this evidence seems to show that phosphorylation (a normal healthy process in other proteins) may somehow be harmful to the α-synuclein protein in PD. Not only that the findings lay the groundwork for further testing of how α-synuclein clumps form, and for finding therapies that would prevent this process from happening in PD. For instance, if we could find a way to stop α-synuclein phosphorylation, might this suggest ways of slowing or stopping PD itself?
Dr. Spinelli has one year of PDF funding remaining. What’s next? “Comparing what’s going on in the brain with behavior, in individual animals, is something you can do only with this technology,” says Dr. Spinelli. For example, in one line of future research, she will test different drugs that target the α-synuclein phosphorylation process to see if they affect PD symptoms in the mice. This might provide clues about treatments that could one day help people living with PD.
Overall, Dr. Spinelli’s research is helping to solve a fundamental piece of the PD puzzle and providing “an opportunity to test some potential disease-modifying therapies.” She noted that having three years of uninterrupted funding from PDF to explore the potential of the project has been “hugely valuable.”
As she put it to PDF News & Review, “Ultimately, if we can figure out what is going on in a living mouse brain, we can apply this to studying what’s going on in people living with Parkinson’s disease.”