PDF-Funded Research Into Alpha-Synuclein
Alpha-synuclein Aggregation Causes Toxicity by Decreasing Functional Forms of the Protein
Matthew Benskey, Ph.D., mentor: Fredric P. Manfredsson, Ph.D., Michigan State University
Alpha-synuclein Mediated Toxicity in the Aged Rat Brain Molecular Mechanism of the Nucleus
Ivette Martinez Sandoval, Ph.D., mentor: Timothy Collier, Ph.D., Michigan State University
Novel Insights into the Properties and Fate of Naturally Secreted Alpha-synuclein
Georgia Sotiropoulou, Ph.D., University of Patras
Phosphorylated Alpha-synuclein Peptides as Biomarkers of Parkinson’s Disease
Li Yang, Ph.D., mentor: Jing Zhang, M.D., Ph.D., University of Washington
A Protein and Parkinson's: Rewards From PDF's 20-Year Investment to Understand Alpha-Synuclein
For almost two decades in our continuing quest to understand and end Parkinson’s disease (PD), the protein known as alpha-synuclein has remained a consistent focus of scientific attention. In fact, researchers consider it to be a prime “smoking gun” in PD — their biggest clue in solving the mysteries of how PD begins and how we might stop it.
We now know that in rare instances, mutations in the alpha-synuclein gene cause inherited forms of Parkinson’s. We also know that changes in the shape of the protein cause it to clump together into something called Lewy bodies. These clumps — in turn — can kill the type of brain cells that are lost in PD, called dopamine neurons.
Many questions remain about alpha-synuclein’s role in causing PD, but the details are becoming clearer. Among the discoveries, we are finding clues for potential PD therapies that target alpha-synuclein, some of which are already in the early stages of clinical trials.
How did we get here? The answer, in part, comes out of PDF’s philosophy of long-term investment in basic research and our support for career development for Parkinson’s scientists. PDF-supported investigators — some of them based at PDF research centers, others selected to receive individual grant awards — have achieved major milestones in our understanding of alpha-synuclein and helped to set the priorities for Parkinson’s disease research around the world. Here’s what we know and where we’re going next.
1962 - 1997 Milestone: Genetic Mutations Can Cause Parkinson’s Disease
The story of alpha-synuclein goes back almost to the founding of PDF in 1957 by William Black, whose generosity created a Parkinson’s disease research laboratory at Columbia University Medical Center. In 1962, Roger Duvoisin, M.D., was selected by PDF — the first of more than 150 such Fellows whose training has been supported by PDF over the years.
At the time, according to textbooks, Parkinson’s disease was thought to result from some unknown environmental cause. But by the 1990s, after he had moved to Robert Wood Johnson Medical School in New Jersey, Dr. Duvoisin began to suspect that genetics played a role. He found Lewy bodies in the brain cells of one of his patients who had died in an accident — a person with PD who had a brother and another relative with PD.
At that time, Lewy bodies were already well-known as a hallmark of Parkinson’s, visible only on autopsy. But scientists didn’t understand what Lewy bodies were made of or how they worked. With colleagues, Dr. Duvoisin tracked down additional members of this family and ultimately traced them all back to a couple who lived in the Italian town of Contursi in the late 1600s. Of their 400 known descendants, 61 – a markedly disproportionate number — were found to have, or have had, PD.
Along with other researchers, Dr. Duvoisin collected blood samples from members of this family and analyzed their DNA. He discovered that they all had the same mutation in the gene for alpha-synuclein, a finding that he and his team published in 1997.
“It was an earthquake in Parkinson research,” recalls William T. Dauer, M.D., then a faculty member at Columbia, who is now at the University of Michigan Medical School, in Ann Arbor. “Out of the blue comes this gene for PD. But it remained totally unclear what its discovery meant for the 95 to 99 percent of people who don’t have the mutation. Discovering the answer to this question has been a major focus of our work ever since.”
It didn’t take long for the broader significance of alpha-synuclein to be recognized. Soon, other scientists realized that the gene identified by Dr. Duvoisin was associated with other well-known brain changes in PD.
After his landmark study, another group of scientists reported that alpha-synuclein was also the major component of Lewy bodies, the hallmark of PD found in the brains of those living with the disease. Then, in 2003, researchers at the National Institutes of Health linked a second genetic change in alpha-synuclein to PD. They found that in people who had three copies of the gene rather than two, brain cells produced too much of the protein, which they thought might be harmful.
Soon after these studies, alpha-synuclein took off as a major focus of research. Many questions remained. For example, what does normal alpha-synuclein do to keep the brain healthy? What goes wrong in PD? And does the protein shed light on cases where there is no family history or genetic cause of PD?
2002 Milestone: Faulty Alpha-synuclein Harms Brain Cells
Dr. Dauer, quoted earlier, was among the first to investigate these questions. As a postdoctoral fellow at the PDF Research Center at Columbia University Medical Center, he undertook a groundbreaking study that began to reveal how alpha-synuclein works inside brain cells.
Dr. Dauer studied laboratory mice whose alpha-synuclein gene had been removed — a method commonly used to understand how genes work. He exposed the mice to a toxin called MPTP that is known to harm dopamine neurons and cause PD-like movement symptoms. Yet, the mice were unaffected. This gave him a clue: the alpha-synuclein gene is a decisive factor in determining the susceptibility of mice to the effects of MPTP.
As he describes it, the study, “showed that alpha-synuclein is involved in the susceptibility of neurons to certain risk factors. It links the biology of the protein to whether a cell lives or dies.” The finding also showed that genes and environmental toxins may affect similar pathways in PD, providing additional clues about what causes PD. “Our paper is just one of the ways in which PDF has helped advance my research,” Dr. Dauer says.
2004 Milestone: Faulty Alpha-synuclein Disrupts Cell Recycling
Dr. Dauer’s research raised another question: if too much alpha-synuclein causes problems for brain cells, then why don’t the brain cells simply get rid of it? In a landmark study published in 2004 (and supported in part by PDF), Ana Maria Cuervo, M.D., Ph.D., and David Sulzer, Ph.D., offered an answer: mutated alpha-synuclein disrupts cellular recycling in Parkinson’s.
The body’s cells, including its brain cells, normally use a process called autophagy to recycle or dispose of worn-out proteins. This process is so important that the scientist who discovered it, Yoshinori Ohsumi, Ph.D., was honored with the 2016 Nobel Prize in Physiology or Medicine. During the process, materials are carried to the recycling center of the cell, the lysosome. Dr. Cuervo, at Albert Einstein College of Medicine in New York City, and Dr. Sulzer, at PDF’s Research Center at Columbia University Medical Center, also in New York, found that mutant alpha-synuclein essentially clogs the lysosome, the chute through which garbage normally enters.
Then, Drs. Cuervo and Sulzer made another finding: that disruptions in autophagy are linked to the build-up of alpha-synuclein in Lewy bodies, and to the PD gene called LRRK2. These fundamental discoveries have led other scientists to investigate potential therapies that might kick-start the recycling process.
2008 Milestone: What Causes Parkinson’s Disease? A New Direction
In 2003, while researchers were working to under- stand how and why the alpha-synuclein protein wreaks havoc within brain cells, a German scientist named Heiko Braak, M.D., proposed a startling theory about how Parkinson’s progresses. Based on his observations of Lewy bodies throughout the body, Dr. Braak suggested that Parkinson’s may begin in nerve cells of the gut and spread from there to the brain. But he offered no explanation for how alpha-synuclein might move from cell to cell.
Seeking a way to show such transmission, in 2008, Jeffrey H. Kordower, Ph.D., working at the PDF Research Center at Rush University Medical Center in Chicago, IL, examined cells that had been transplanted into the brains of people with PD as an experimental therapy intended to replace lost dopamine neurons. His key finding: over a period of about 10 years, the transplanted cells themselves developed Lewy bodies. This provocative finding raised a crucial question: why and how would perfectly healthy cells — cells designed to replace the dying cells — also develop the hallmark of PD?
“What we saw, led us to suspect that it’s not just a matter of a brain cell accumulating its own alpha-synuclein,” Dr. Kordower said. “Instead, alpha-synuclein comes from the unaffected cell, and then spreads from cell to cell.” Investigation of this potential “infectious” spread of alpha-synuclein has become an intense area of research today. Dr. Kordower’s study ultimately helped provide a basis for clinical trials now under way, testing whether antibodies can mop up alpha-synuclein outside of cells and thereby slow Parkinson’s progression.
The Road Ahead
Over two decades, PDF’s patient investment in basic science and in training young scientists has helped keep alpha-synuclein at the forefront of investigation. “PDF has been really important in making this happen — research that has stood the test of time,” says Dr. Dauer.
Today more than a dozen genes have been identified that, in their mutated form, contribute to PD. What’s more, researchers have found that many of these other genes interact with alpha-synuclein inside cells — for example, as part of autophagy. In addition, subtle, non-inherited changes in alpha-synuclein are now known to enhance a person’s risk of developing Parkinson’s.
PDF continues to support research that reveals the normal role of alpha-synuclein and what goes awry in PD, including awarding several grants to individuals as well as to long-term research at PDF’s Research Centers. Many lines of research are converging on alpha-synuclein, and these studies will be providing the necessary knowledge from which to find better ways to diagnose and treat PD, and ultimately, to prevent it.