Blocking GPNMB Protein Could Slow Parkinson's Spread Through the Brain, Early Study Finds

Parkinson's disease is often caught early, while the tremor is mild and walking is still steady. Even then, no approved treatment can slow what comes next. That gap is what Alice Chen-Plotkin, MD, the Parker Family Professor of Neurology, and her colleagues are working on. Their latest study points to a protein called glycoprotein nonmetastatic melanoma B, or GPNMB, as a possible driver of the disease's advance through the brain.

The disease affects more than one million Americans, and roughly 90,000 people in the United States are diagnosed each year. Researchers still do not fully understand its cause. They have known for years, though, that it moves through the brain in stages. A protein called alpha-synuclein is central to that movement. In Parkinson's, it forms abnormal clumps inside neurons, which damage the cells that carry them. The clumps can then pass into nearby healthy neurons and keep spreading.

As more regions are affected, symptoms accumulate: tremors, difficulty walking, balance problems and trouble swallowing. Levodopa and deep-brain stimulation can ease those symptoms. But no approved therapy has been shown to slow or stop the underlying progression.

Chen-Plotkin and her colleagues had already identified GPNMB in 2022 as a molecule involved in the spread of alpha-synuclein between neurons. The new study asks where it comes from. The team found that microglia, the brain's immune cells, are a major source in Parkinson's disease. When neurons are damaged or dying, nearby microglia make more of the protein. Enzymes then cut part of GPNMB away from the cell surface, letting it move freely between cells.

The researchers then built antibodies designed to block GPNMB and tested them in laboratory experiments with cultured neurons. The antibodies prevented alpha-synuclein pathology from passing from one cell to another.

Chen-Plotkin describes a self-reinforcing cycle. Alpha-synuclein accumulates in neurons and injures them. The injury prompts GPNMB release, which speeds the spread of alpha-synuclein and causes further damage. Interrupting that loop, she said, would hopefully slow or even stop the spread of alpha-synuclein and the neurodegeneration that follows.

To see whether the findings held up in people, the team analyzed tissue from 1,675 brains stored in the Penn Brain Bank. Individuals carrying genetic variants linked to higher GPNMB production also showed more extensive alpha-synuclein pathology. The researchers say this is strong evidence that GPNMB contributes to progression in humans. Elevated GPNMB was not tied to markers of other neurodegenerative conditions, including Alzheimer's disease.

The work remains preclinical. Chen-Plotkin was plain about that: the results are promising in lab models and human brain tissue, but much work remains before a therapy could be translated to patients. The study was supported by the National Institutes of Health, SPARK-NS, the Parker Family Chair and the Lipman Family Fund. What to watch for is whether GPNMB-blocking antibodies can move beyond cultured neurons into further testing.