A protein called GPNMB may explain how Parkinson’s disease pathology spreads from one brain cell to the next — and blocking it with an antibody appears to interrupt that spread, according to a study published in Neuron by researchers at the University of Pennsylvania’s Perelman School of Medicine.
The paper, “Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies” (Carceles-Cordon et al., Neuron, May 12, 2026), was led by Alice S. Chen-Plotkin’s lab, with co-authors including Vivianna Van Deerlin, Edward B. Lee, Kurt Brunden and Kelvin C. Luk, and collaborators at the Whitehead Institute (Rudolf Jaenisch).
What the study found
Parkinson’s disease is defined pathologically by the spread of misfolded alpha-synuclein protein through the brain, cell by cell, as the disease progresses. Exactly how alpha-synuclein moves between neurons — rather than simply accumulating within a single cell — has been a central open question in the field.
The Penn team found that GPNMB (glycoprotein nonmetastatic melanoma protein B), a protein already known as an immune-response marker, is secreted in a soluble, extracellular form that helps neighboring neurons take up pathological, fibrillar alpha-synuclein — a “non-cell-autonomous” mechanism, meaning the damage isn’t confined to the cell that produces the protein. The researchers also reported that microglia (the brain’s resident immune cells) increase GPNMB expression when exposed to dying neurons, and that, across a set of more than 1,600 postmortem brain samples, higher-GPNMB genotypes correlated with more extensive alpha-synuclein pathology.
Critically, when the team applied monoclonal antibodies against GPNMB in cultured neurons, the antibodies blocked the uptake of pathological alpha-synuclein — interrupting the cell-to-cell transmission step in the lab.
The proposed self-reinforcing cycle
In a Penn Today announcement of the findings, Chen-Plotkin, the Parker Family Professor of Neurology at the Perelman School of Medicine, described the mechanism the team believes is at work:
“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. Interrupting this cycle would hopefully slow, or even stop, the spread of alpha-synuclein through the brain and the neurodegeneration that follows.”
That framing is what makes GPNMB attractive as a drug target: rather than trying to clear alpha-synuclein aggregates directly — the strategy behind several antibody trials that have so far shown limited clinical benefit — an anti-GPNMB antibody would aim to break the propagation step itself, potentially slowing disease progression rather than just addressing existing damage.
The current findings are from cultured-neuron and postmortem-tissue studies, not a clinical trial. Translating a blocking antibody into a therapy that is safe and effective in living patients — including getting an antibody past the blood-brain barrier at a meaningful concentration — is a substantial additional step that has not yet been reported.
The funding: specific NIH grant numbers
The published paper’s funding acknowledgment credits several NIH awards: P01 AG084497, R01 NS115139, R37 NS115139, and T32 AG000255 — a mix of a program-project grant, R01/R37 research grants, and an institutional training grant, reflecting the multi-investigator, multi-year nature of the work. For research-administration audiences, it’s a useful illustration of how NIH’s Grants Policy Statement-governed award mechanisms stack on a single paper: a P01 program project, standard and MERIT-extension (R37) R01-track awards, and a T32 training grant supporting the graduate and postdoctoral trainees on the author list all had to be separately administered, reported, and acknowledged.
Why it matters for Parkinson’s research funding and administration
Parkinson’s disease affects an estimated one million people in the U.S. and its prevalence is projected to keep rising as the population ages, making cell-to-cell spread mechanisms like this one a high-priority target for NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA) portfolios — both of which funded grants acknowledged in this paper. Research offices tracking neurodegeneration-adjacent funding opportunities, or administering multi-mechanism awards spanning P01, R01/R37, and T32 grants on a single project, may find this paper a useful concrete example of how those award types combine in practice. See CASRAI’s guide to the NIH Parent R01 funding mechanism for background on how standing R01 announcements work alongside program-project and training grants.
Sources
- Carceles-Cordon M, Brody EM, Boucher ML, et al. “Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies.” Neuron, May 12, 2026. DOI: 10.1016/j.neuron.2026.04.033
- Penn Today: “Immune Protein a Possible Target to Slow Parkinson’s Disease”, May 22, 2026
