Managing Misfolded Proteins to Prevent Parkinson’s Disease

The protein alpha-synuclein is abundant in healthy brains and plays an important role in enabling communication between nerve cells. However, under certain conditions, misfolded alpha-synuclein proteins can accumulate into toxic clumps inside neurons. Known as Lewy bodies, these clusters of proteins are a hallmark of Parkinson’s disease and some forms of dementia.

In recent years, researchers have discovered that these misfolded proteins don’t just stay in one place: They spread from one cell to another through the fluid spaces of the brain.

“Once it starts piling up in one neuron and causing disease, it can get out of cell one and get into cell two,” says Stephen Strittmatter, MD, PhD, Vincent Coates Professor of Neurology and professor and chair of neuroscience. “And so it spreads through the brain.”

In a new team science project funded by Aligning Science Across Parkinson’s (ASAP), Yale School of Medicine researchers hope to shed new light on what happens to alpha-synuclein in between nerve cells—and what determines where it ends up.

“What is its fate?” Strittmatter asks. “What is the balance between moving it out of the brain versus being taken up into another neuron and spreading disease?”

To try to find that balance, Strittmatter and colleagues plan to approach the problem from different angles.

The first step in this work was to determine which proteins in the nerve cells were responsible for attaching to and picking up the misfolded alpha-synuclein. Strittmatter says it was something like finding a handful of needles in a haystack. “Out of five or six thousand proteins that we screened, we did find about 15 proteins that could bind labeled synuclein,” he recalls. “Meaning there were over 5,000 that didn't.”

Of that handful of proteins, researchers focused on the only two that were selectively expressed in the dopamine-containing neurons most impacted by Parkinson’s: metabotropic glutamate receptor 4 (mGluR4) and NPDC1.

In preclinical models, researchers found genetically “knocking out” either or both proteins prevented the deaths of dopamine-related neurons usually seen in Parkinson’s disease. Strittmatter hopes mGluR4, in particular, could represent a target for future treatments.

“So far, we've just knocked out the gene completely,” he says, “but delivering a drug that targets the mGluR4 protein at different time points would give us a lot more information about its potential as a therapeutic target and the timing of mGluR4's role in the whole disease.”

While Strittmatter’s team tries to prevent neurons from taking up the misfolded proteins, a team led by Eric Song, MD, PhD, assistant professor of ophthalmology & visual sciences and of immunobiology, will investigate the other side of the equation: how lymphatic vessels work to clear and drain the protein before it can bind to nerve cells.

“Lymphatics are designed to clear metabolic, inflammatory, even protein waste from organs,” he explains. “So that's really where my portion comes into play, looking at the lymphatic clearance of extracellular alpha-synuclein.”

The researchers say helping the lymphatic system clear faulty proteins, while also limiting their uptake by nearby nerve cells, could help slow or prevent the spread of disease. Song says it’s just the kind of bold strategy the ASAP grants are designed to promote.

“It kind of pushes you to do the big and bold experiments that you won't be able to do otherwise,” he says. “And that's where I think, instead of the incremental changes, the big leaps actually happen.”

Song spun off the biotechnology start-up Rho Bio in 2024 to treat eye diseases by targeting the lymphatic system. In the years since, he says, lymphatic agonists have shown promise for neurodegenerative conditions like Alzheimer’s disease as well. Now, he hopes the same mechanism could be used in the fight against Parkinson’s.

“It was a natural progression,” Song says, “to use the same lymph-based mechanism in Parkinson’s disease because the pathological formation of a proteinopathy is parallel to that of Alzheimer’s disease.”

Current preclinical models of Parkinson’s disease involve introducing alpha-synuclein fibrils into mouse brains or modifying mouse genes so that mice make too much alpha-synuclein. But neither of these models accurately mimics the extracellular alpha-synuclein Strittmatter’s team hopes to study.

As luck would have it, a Yale School of Medicine team led by Le Zhang, PhD, assistant professor of neurology and of neuroscience, was already on the verge of a new preclinical Parkinson’s disease model that more closely mirrors the human progression of the disease. “It's a translational model that can link to the patient themselves,” Zhang explains, “not just the one gene or one artificial thing.”

Zhang’s team found infusions of human cerebrospinal fluid (CSF) from patients with Parkinson’s disease caused Parkinson’s-like symptoms in mice over time, including alpha-synuclein aggregation in the mouse brains. That means it’s a model that can tell us more about how treatments might work in humans. But Zhang says it may also tell us something important about the mechanism of disease.

“In our current hypothesis, it could be an immune complex involving pathogenic alpha-synuclein and human autoantibodies all together,” she says. “They may form an immune complex in the CSF that drives the disease.”

When the three teams realized they were each working independently on alpha-synuclein outside neurons, the full scale of the project started taking shape.

“Each of the three projects sort of started independently,” Strittmatter recalls. “But then we recognized that there was real overlap or synergy between thinking about extracellular synuclein in a holistic way.”

The researchers hope their findings could point the way back to that all-important balance: treatments that could help reduce the amount of alpha-synuclein being picked up by neurons while ensuring more of the proteins are cleared and drained before they can become a problem.

Strittmatter says that work is already underway, in collaboration with teams at Columbia and Vanderbilt universities. “The group at Vanderbilt has done a whole lot of drug discovery, particularly on metabotropic glutamate receptors, but haven't looked at synuclein effects,” he says. “So we're going to work with them to see if we can find any compounds.”

Researchers say their work on lymphatic drainage could also lead to breakthroughs for patients living with conditions like Alzheimer’s disease.

“There's been a lot of research and discussion about lymphatics affecting sleep quality,” says Song. “And there are ties into how sleep is important in Alzheimer's and Parkinson's, so now we're integrating our research to think about sleep in these patients, both in terms of clinical trials and helping patients have less severe disease.”