Summary: Researchers identified a promising new target for slowing the progression of Parkinson’s disease (PD). The study demonstrates that a protein called GPNMB (glycoprotein nonmetastatic melanoma B) acts as a catalyst for the spread of toxic alpha-synuclein clumps between neurons.
By using monoclonal antibodies to block this protein, scientists were able to interrupt the cycle of damage in preclinical models, offering a potential path toward the first disease-modifying therapy for PD.
Key Research Findings
- The Alpha-Synuclein Driver: Parkinson’s progresses as abnormal clumps of alpha-synuclein move from affected neurons to healthy ones, leading to cell death and worsening symptoms like tremors.
- The Role of Microglia: The brain’s immune cells, microglia, are a major source of GPNMB. When neurons are injured, microglia increase GPNMB production; enzymes then release the protein, allowing it to move freely and accelerate the spread of pathology.
- A Self-Reinforcing Cycle: The study suggests PD is driven by a feedback loop: alpha-synuclein damages neurons, which triggers the release of GPNMB, which in turn speeds up the spread of alpha-synuclein to more neurons.
- Human Evidence: Analysis of 1,675 brains from the Penn Brain Bank showed that individuals with genetic variants for high GPNMB production had more extensive alpha-synuclein pathology.
- Specificity: Elevated GPNMB levels were specifically linked to Parkinson’s and were not associated with markers for other neurodegenerative conditions like Alzheimer’s disease.
Source: University of Pennsylvania
Monoclonal antibodies can block a key immune‑related protein that drives the spread of brain cell damage in Parkinson’s disease (PD).
This protein, called glycoprotein nonmetastatic melanoma B (GPNMB), might be part of a promising strategy for developing a treatment that slows disease progression at its earliest stages, according to a new study published today in Neuron, from researchers at the Perelman School of Medicine at the University of Pennsylvania.
“Many patients with Parkinson’s disease are diagnosed in the early stages, when symptoms are relatively mild, but there is currently no treatment that slows the progression,” said lead author, Alice Chen‑Plotkin, MD, Parker Family Professor of Neurology.
“These early results are a promising step towards developing this type of treatment.”
How Parkinson’s disease spreads through the brain
PD affects more than one million people in the United States, with roughly 90,000 new diagnoses each year. While the exact cause of the disease remains unclear, scientists have long known that PD spreads through the brain in stages.
This progression is driven by abnormal clumps of a neuronal protein called alpha‑synuclein. These clumps accumulate inside affected neurons, contributing to their dysfunction and death, and are then released and taken up by nearby healthy neurons.
As this pathology moves through different brain regions, patients experience the worsening symptoms that characterize PD, like tremors and difficulty walking or swallowing.
While there are a number of medications and therapies that can help improve the symptoms of PD—ranging from a drug called levodopa to deep-brain stimulation delivered through an implanted electrode—there is no existing treatment that slows the progression of PD.
Identifying immune cells as an unexpected therapy
In earlier work published in 2022, Chen‑Plotkin and colleagues identified GPNMB as a key molecule involved in the neuron‑to‑neuron spread of alpha‑synuclein pathology, making it a compelling therapeutic target.
In this new study, the researchers discovered that microglia, the brain’s resident immune cells, are a major source of GPNMB related to Parkinson’s disease. When microglia are near injured or dying neurons, they produce increased amounts of GPNMB. Enzymes then separate the protein from the cell surface, releasing part of it to move freely between cells.
In preclinical experiments using cultured neurons, Chen-Plotkin developed antibodies that block GPNMB prevented the spread of alpha‑synuclein pathology from cell to cell.
“These results suggest Parkinson’s disease may be driven by a self reinforcing cycle—alpha-synuclein accumulates in neurons, damaging the neurons. The injury to the neurons initiates the release of GPNMB, which accelerates the spread of alpha-synuclein, leading to further damage,” Chen‑Plotkin said.
“Interrupting this cycle would hopefully slow, or even stop, the spread of alpha-synuclein through the brain and the neurodegeneration that follows.”
Charting a potential path toward disease modifying therapy
To assess the relevance of these findings in people, the team analyzed tissue from 1,675 brains in the Penn Brain Bank. Individuals with genetic variants associated with higher GPNMB production showed more extensive alpha‑synuclein pathology, providing strong human evidence that the protein plays a central role in disease progression. What’s more, elevated levels of GPNMB were not associated with the markers of other neurodegenerative diseases like Alzheimer’s disease.
“These results are promising for laboratory models and human brain tissue analysis, but we still have a lot of work to do before we can translate this therapy into humans,” said Chen-Plotkin. “That being said, these results are encouraging as we continue to work towards a novel treatment for PD.”
Funding: This study was supported by the National Institutes of Health (R37 NS115139, P30 AG010124, U19 AG062418, P01 AG084497), SPARK‑NS, the Parker Family Chair, and the Lipman Family Fund.
Key Questions Answered:
A: Current treatments, like levodopa, only manage symptoms, they don’t stop the underlying brain damage. This antibody therapy aims to be “disease-modifying,” meaning it could actually slow or stop the physical spread of the disease through the brain.
A: The monoclonal antibodies developed by the researchers bind to the GPNMB protein. By latching onto GPNMB, they prevent it from interacting with neurons and spreading the toxic alpha-synuclein “seeds” to healthy cells.
A: Not yet. While the results in laboratory models and human tissue analysis are highly encouraging, the researchers emphasize that more work is needed before this can be translated into human clinical trials.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Parkinson’s disease research news
Author: Eric Horvath
Source: University of Pennsylvania
Contact: Eric Horvath – University of Pennsylvania
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies” by Marc Carceles-Cordon, Eliza M. Brody, Masen L. Boucher, Michael D. Gallagher, Robert T. Skrinak, Travis L. Unger, Cooper K. Penner, Adama J. Berndt, Sromona Das, Katie Lam, Rudolf Jaenisch, Vivianna Van Deerlin, Edward B. Lee, Kurt Brunden, Kelvin C. Luk, and Alice S. Chen-Plotkin. Neuron
DOI:10.1016/j.neuron.2026.04.033
Abstract
Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies
Glycoprotein nonmetastatic melanoma B (GPNMB) is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein in Parkinson’s disease (PD).
Here, we demonstrate that the non-membrane-anchored, extracellular domain of GPNMB can function in a non-cell-autonomous manner. In the human brain, GPNMB is widely expressed in neurons and microglia. In induced pluripotent stem cell-derived microglia (iMicroglia), GPNMB expression and secretion increase with exposure to apoptotic neurons.
In the aSyn fibril-seeded model of PD, iMicroglia-derived GPNMB enhances neuronal aSyn uptake and development of aSyn pathology, including in GPNMB knockout neurons. Conversely, anti-GPNMB antibodies rescue neurons from developing aSyn pathology. Finally, in 1,675 human postmortem cases, GPNMB genotypes conferring higher GPNMB expression are associated with more widespread aSyn pathology.
Our data suggest a positive feedback loop, where neurodegeneration triggers increased microglial GPNMB secretion, leading to increased neuronal aSyn pathology and neurodegeneration. Importantly, this cycle can be therapeutically interrupted by anti-GPNMB antibodies.
