Researchers at the Perelman School of Medicine at the University of Pennsylvania have identified a brain immune protein that may play a key role in the progression of Parkinson’s disease (PD). Their findings were; neuronsuggest that blocking this protein with monoclonal antibodies could ultimately lead to treatments that slow the progression of the disease in its early stages.
The protein, known as glycoprotein nonmetastatic melanoma B (GPNMB), appears to help harmful Parkinson’s disease-related damage spread from one brain cell to another. Scientists say targeting this could provide a new strategy to slow the disease’s worsening over time.
“Many people with Parkinson’s disease are diagnosed at an early stage when symptoms are relatively mild, and there are currently no treatments available to slow progression,” said lead author Alice Chen Plotkin, MD, PhD, Parker Family Professor of Neurology. “These early results are a promising step toward developing this type of therapy.”
How Parkinson’s disease spreads in the brain
Parkinson’s disease affects more than 1 million Americans, and approximately 90,000 people are diagnosed with Parkinson’s disease each year. Although researchers still do not fully understand the cause of the disease, they have known for years that the disease spreads to the brain gradually in stages.
A protein called alpha-synuclein is central to this process. In Parkinson’s disease, alpha-synuclein forms abnormal clumps within neurons. These clumps damage affected cells and then migrate to nearby healthy neurons, where they continue to spread.
Symptoms worsen as more areas of the brain are affected. Patients may develop tremors, difficulty walking, balance problems, and difficulty swallowing.
Current treatments such as levodopa and deep brain stimulation can help reduce symptoms. However, there are no approved treatments that slow or stop the underlying progression of Parkinson’s disease itself.
Brain immune cells may promote disease progression
In a previous study published in 2022, Chen-Plotkin and colleagues identified GPNMB as a key molecule involved in the spread of alpha-synuclein between neurons. This discovery makes this protein a promising target for future treatments.
In a new study, a team of researchers found that the brain’s immune cells, microglia, are the main source of GPNMB in Parkinson’s disease. When neurons become damaged or begin to die, nearby microglia respond by producing large amounts of protein.
Enzymes then detach part of GPNMB 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. This antibody was successful in preventing alpha-synuclein pathology from spreading between cells.
“These results suggest that Parkinson’s disease may be caused by a self-reinforcing cycle, in which alpha-synuclein accumulates within neurons and damages them. Damage to neurons initiates the release of GPNMB, which accelerates the spread of alpha-synuclein and leads to further damage,” Chen-Plotkin said. “By interrupting this cycle, we hope to be able to slow or even stop the spread of alpha-synuclein through the brain and the subsequent neurodegeneration.”
Analysis of human brain confirms findings
To see if the results were relevant to humans, the researchers analyzed 1,675 brain tissue samples held at the Penn Brain Bank.
The research team found that individuals who carried genetic variations associated with increased production of GPNMB also exhibited broader alpha-synuclein pathology. According to the researchers, this provides strong evidence that GPNMB plays an important role in the progression of Parkinson’s disease in humans.
Importantly, elevated GPNMB levels were not associated with markers associated with other neurodegenerative conditions, including Alzheimer’s disease.
“While these results are promising for laboratory models and human brain tissue analysis, there is still much work to be done before this therapy can be applied to humans,” Chen-Plotkin said. “That said, these results are encouraging as we continue to work towards new treatments for PD.”
This research 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 Foundation.
