GPNMB Protein May Be Parkinson’s Biomarker, Treatment Target: Study

Levels of a protein called glycoprotein nonmetastatic melanoma protein B (GPNMB) are elevated in the blood of people with Parkinson’s disease, indicating the protein may be a biomarker for the neurological disorder, according to a new study.

GPNMB also helps to promote the toxic aggregation of alpha-synuclein protein in nerve cells, which is thought to contribute to neurodegeneration in Parkinson’s, suggesting it could also be a potential treatment target.

the study,”GPNMB confers risk for Parkinson’s disease through interaction with a-synuclein,” was published in Science.

The causes of Parkinson’s disease remain incompletely understood, but genetics are known to play a role. Much of what’s known about how genetics affects Parkinson’s risk comes from genome-wide association studies (GWAS) — large analyzes that basically test whether a given genetic variation is more common in people with Parkinson’s than in the general population.

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Prior GWAS analyzes indicated that a particular genetic variation on chromosome 7, called rs199347, is disproportionately common among Parkinson’s patients, implying that this variant increases Parkinson’s risk. The biological implications of this variant have been unclear.

Here, scientists conducted a battery of detailed genetic analyzes to confirm prior findings that the rs199347 variant is linked with Parkinson’s risk then zeroed in on the exact gene associated with this variant, called GPNMBwhich codes for a protein of the same name.

Analyzes of brain tissue from four people with Parkinson’s and two without the disorder showed that levels of GPNMB protein were roughly three times higher across brain regions in people with the Parkinson’s-associated variant (regardless of whether or not they had Parkinson’s disease). Collectively, these data suggest elevated levels of GPNMB protein increase Parkinson’s risk.

The scientists next generated human nerve cells engineered to have normal, reduced, or completely absent GPNMB levels. Using these cell models, the team assessed the impact of GPNMB on alpha-synuclein. Reducing GPNMB levels led to a marked reduction in levels of alpha-synuclein at the connections between nerve cells, called synapses.

Further cellular and computational analyzes showed the GPNMB and alpha-synuclein proteins can physically interact with each other, and suggested alpha-synuclein also interacts with many proteins whose activities are impaired in cells lacking GPNMB.

In Parkinson’s disease, alpha-synuclein forms fibrils or clumps in nerve cells which are toxic and are thought to be a major driver of nerve cell dysfunction in the disease. These clumps normally can spread from cell to cell, driven in part by neurons taking in alpha-synuclein from neighboring cells.

When the researchers treated wild-type nerve cells with fibrillar alpha-synuclein, the cells readily internalized substantial amounts of the toxic protein, leading to the formation of further clumps inside them. However, this internalization and clumping was markedly reduced in cells with low or no GPNMB.

In other cell lines that don’t normally take up fibrillar alpha-synuclein, increasing GPNMB levels led the cells to internalize the toxic protein.

These findings “support a model in which higher GPNMB expression levels confer risk for PD [Parkinson’s disease] through interactions with aSyn [alpha-synuclein] that are permissive for neuronal internalization of fibrillar aSyn,” the researchers concluded.

The research team speculated that targeting GPNMB to block the spread of disease-associated alpha-synuclein might be a useful treatment strategy for Parkinson’s, though they emphasized that more research is needed to verify and expand the results.

“What remains to be seen is whether GPNMB interacts with both normal and pathological [disease-causing] conformations of aSyn to a similar extent and whether our neuronal findings will translate in vivo [living animals],” the researchers noted.

In a final set of experiments, they measured GPNMB levels in samples of blood and cerebrospinal fluid (CSF) – the liquid around the brain and spinal cord – in 731 Parkinson’s patients and 59 people without the disease.

Results showed average blood GPNMB levels were significantly higher among Parkinson’s patients and tended to be higher in those with more severe motor symptoms. No statistically significant associations were seen with CSF levels of BPNMB.

These findings suggest “that GPNMB could be a biomarker of disease progression,” a pair of scientists in Germany wrote in an accompanying perspective paper. They emphasized, however, that further work is needed to validate these findings, to compare GPNMB levels in Parkinson’s to other related neurological disorders, and to test whether the protein is useful for detecting Parkinson’s in its earliest stages.

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