The protein, known as glycoprotein nonmetastatic melanoma B (GPNMB), appears to help harmful Parkinson's-related damage spread from one brain cell to another. Scientists say targeting it may offer a new strategy for slowing the worsening of the disease over time.

"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 in the Brain

Parkinson's disease affects more than one million Americans, and approximately 90,000 people in the United States are diagnosed each year. Although researchers still do not fully understand what causes the disease, scientists have known for years that it gradually spreads through the brain in stages.

A protein called alpha-synuclein is central to this process. In Parkinson's disease, alpha-synuclein forms abnormal clumps inside neurons. These clumps damage the affected cells and can then move into nearby healthy neurons, where they continue spreading.

As more areas of the brain become affected, symptoms worsen. Patients may develop tremors, difficulty walking, balance problems, and trouble swallowing.

Current treatments, including levodopa and deep-brain stimulation, can help reduce symptoms. However, no approved therapy has been shown to slow or stop the underlying progression of Parkinson's disease itself.

Brain Immune Cells May Help Fuel Disease Progression

In earlier research published in 2022, Chen-Plotkin and colleagues identified GPNMB as an important molecule involved in the spread of alpha-synuclein between neurons. That discovery made the protein a promising target for future therapies.

In the new study, the research team found that microglia, the brain's immune cells, are a major source of GPNMB in Parkinson's disease. When neurons become damaged or begin dying, nearby microglia respond by producing larger amounts of the protein.

Enzymes then cut part of GPNMB away from the cell surface, allowing it to move freely between cells in the brain.

Using preclinical laboratory experiments with cultured neurons, researchers developed antibodies designed to block GPNMB. The antibodies successfully prevented alpha-synuclein pathology from spreading from one cell to another.

"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."

Human Brain Analysis Supports the Findings

To examine whether the results were relevant in people, researchers analyzed tissue samples from 1,675 brains stored in the Penn Brain Bank.

The team found that individuals carrying genetic variants linked to higher GPNMB production also showed more extensive alpha-synuclein pathology. According to the researchers, this provides strong evidence that GPNMB plays a significant role in the progression of Parkinson's disease in humans.

Importantly, elevated GPNMB levels were not connected to markers associated with other neurodegenerative conditions, including 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."

The study received support from the National Institutes of Health (R37 NS115139, P30 AG010124, U19 AG062418, P01 AG084497), SPARK-NS, the Parker Family Chair, and the Lipman Family Fund.