A Year of Anniversaries: Making Sense of α-Synuclein and Parkinson’s Disease

Two hundred years ago, James Parkinson published “An Essay on the Shaking Palsy,” a medical treatise on the neurodegenerative disorder we now call Parkinson’s disease. Known by its hallmark muscle weakness and shaking tremors, Parkinson’s still has few effective treatments and scientists still don’t fully understand the cause or progression of the disease.

“2017 is an important year. We celebrate the 200 years since the initial report by James Parkinson. We celebrate the 20^th anniversary since scientists first identified α-synuclein Lewy bodies, the brain pathology that we see in the brain with Parkinson’s disease and the first genetic association of the mutation in the α-synuclein gene in Parkinson’s cases,” explained Tiago Fleming Outeiro, director of the department of experimental neurodegeneration at University Medical Center at Goettingen, Germany, and member of the European Dana Alliance for the Brain (EDAB). “Yet we still don’t really know what triggers this neurodegenerative process. We don’t really understand how this disease results in its cognitive symptoms like memory and decision-making problems. We need a lot more basic research to understand what is really going on.”

For the past few decades, many scientists have focused their investigations on the accumulation of α-synuclein in the brain, but what causes the protein to misfold, accumulate, and form Lewy bodies remains elusive. To highlight new basic research findings that may provide clues to help unravel this neuroscientific mystery, Outeiro chaired the session “Alpha-Synuclein: Models and Mechanisms” at Neuroscience 2017, the 47^th annual meeting of the Society for Neuroscience. He said he thinks this work will pave the way for a better understanding of Parkinson’s pathology, its motor and cognitive symptoms, as well as the potential for future biomarkers to help better diagnose, track, and treat the disease.

The Shape of Neurons

Sreeganga Chandra, a neuroscientist at Yale University, said that, while many scientists have looked at reducing the overall amount of α-synuclein in the brain, the protein’s normal physiological function—and how it may influence neurons—is not well understood.

“We know that the synuclein family is a small family of vertebrate proteins. There are three members–alpha, beta, and gamma—and we find them around the synapse,” she said. She then discussed several studies that suggest that the synucleins work as a sort of “membrane curvature sensor,” which influences the function of synaptic vesicles that help to take in molecules (endocytosis) and expel molecules (exocytosis), both processes critical to neurotransmission and overall cell health.

“It’s known all proteins that can actively sense membrane curvature can also generate membrane curvature, meaning they can bend the membrane,” she said. “So we were interested in learning whether a protein is a curvature sensor or a generator is depending on protein concentration.”

Using mice genetically modified with or without each of the three synuclein proteins, Chandra and colleagues looked for changes in neuronal membrane function. They observed that α-synuclein helped facilitate the endocytic process, yet when the researchers then overexpressed α-synuclein in mice, they found that endocytosis was significantly impaired.

“Our work suggests α-synuclein is a regulating endocytic protein,” she said. “When it is overexpressed, it makes changes that can lead to progressive synaptic deficits and ultimately the neurodegeneration we see in Parkinson’s disease.”

Protein Interactions

Outeiro also presented his own research, published in the November 2017 issue of Nature Neuroscience. Several studies now show that α-synuclein accumulation does not occur just in the substantia nigra, the area of the brain usually implicated in Parkinson’s but it spreads across different brain regions.

“You can find α-synuclein in different parts of the brain—even outside the brain, in the gut. It builds up, eventually affecting the substantia nigra. But it’s spreading all over. And this protein spreading is interesting. As it’s floating around in the brain outside of neurons, what might it do to synaptic function?” he said. “If it is floating around in the hippocampus, the area responsible for learning and memory, could it explain some of the cognitive symptoms we see with Parkinson’s disease?”

Previous work in the Alzheimer’s field suggested that a particular protein called PrP^C could recognize and interact with amyloid beta, the protein that builds up into the tell-tale plaques observed in that neurodegenerative disorder. As some have hypothesized that PrP^C‘s function may be to recognize other proteins that are outside the cell and transmit information about them to the cell, Outeiro wondered if PrP^C might also be interacting with α-synuclein, resulting in the clumpy Lewy bodies, in a similar manner. To test the idea, Outeiro and colleagues compared electrophysiological recordings of hippocampal slices from mice who were genetically engineered to not produce PrP^C. When they then added extracellular α-synuclein to the cells in those slices, they found it significantly impaired long-term potentiation (LTP), the synaptic activity that promotes signal transmission between neurons, by setting off molecular cascades that interfered with the cells’ normal homeostasis processes. The researchers were able to stem the process and rescue LTP by simply adding a small caffeine analogue molecule to the cells.

“We found that we could detect the effect of α-synuclein on neuronal function,” Outeiro said. “It actually causes a lot of dysfunction by activating some signaling cascades that eventually lead to alterations in synaptic plasticity. We think this translates into the process of memory formation, which, we believe, is important in the context of the cognitive deficits we see in Parkinson’s disease. But we actually found there are molecules we can use to block this effect. That suggests there are ways we might block the effects of that floating α-synuclein, and improve the cognitive deficits in Parkinson’s patients.”

Finding a Path Forward

Two hundred years ago, in that first clinical description, Parkinson wrote, “The disease is of long duration: to connect, therefore, the symptoms which occur in its later stages with those which mark its commencement, requires a continuance of observation of the same case, or at least a correct history of its symptoms, even for several years.”

But Kristina Herfert, a neuroscientist from Germany’s University of Tuebingen who is currently looking for viable imaging markers of α-synuclein pathology in the brain, hopes that we can develop new imaging paradigms and biomarkers to help us detect the disease earlier and track it as it progresses.

“Clinically relevant biomarkers for this disease are still lacking,” she said. “Especially those that can help doctors diagnose Parkinson’s before too much damage is done to the brain.”

Outeiro agrees—and it’s one the reasons why he is championing more basic science work when it comes to this debilitating neurodegenerative disorder.  Though work on membrane curvature and protein interactions may not seem as important as clinical trials or human studies, Outeiro says this work will provide the foundation upon which scientists will eventually build future interventions for patients.

“This disease is a lot more complicated than we thought it would be—there is still quite a bit we need to understand,” he said. “Having access to the brain is not easy. So we are looking to basic science to help us provide alternative ways for getting an indication that there is something bad going on with patients. With more research, we hopefully will be able to identify the different neural signatures that will enable us to predict who is going to develop Parkinson’s, identify good candidates for clinical trials, follow disease progression, and, with luck, find new opportunities to treat this disorder.”