Study: RAGE Protein Plays Key Role in Parkinson’s Neuroinflammation

Protein found to mediate inflammatory response of brain immune cells

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Scientists have shed new light on the interaction of toxic apha-synuclein clumps — a hallmark of Parkinson’s disease — with microglia, the brain’s immune cells. This interaction was found to be mediated by RAGE, a protein at the surface of microglia, which promoted the release of inflammatory molecules from the cells, according to a study in lab-grown cells.

“Our work shows the important role, as well as the structural mechanism, of RAGE in mediating the inflammatory response of microglia to [alpha-synuclein clumps],” the researchers wrote.

The findings “may help to establish effective therapeutic strategies to alleviate [alpha-synuclein]-induced neuroinflammation and neuronal damage,” they added.

Still, future studies in animal models are need to confirm these findings.

The study, “Interaction of RAGE with α-synuclein fibrils mediates inflammatory response of microglia,” was published in Cell Reports.

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Study Explores New Way to Monitor Neuroinflammation

Parkinson’s is characterized by the toxic buildup of alpha-synuclein fibrils or clumps in nerve cells that are thought to be a major driver of nerve cell dysfunction in the disease.

These toxic fibrils are transmitted between adjacent nerve cells, but also to other cell types, including microglia. While the mechanisms by which it does so are unclear, alpha-synuclein can stimulate the activation of microglia, which then release factors that promote neuroinflammation and further exacerbate nerve cell death.

Role of RAGE protein

Now, a team of researchers in China provided evidence that this process is mediated by a receptor protein at the surface of microglia, called the receptor for advanced glycation end products or RAGE.

This protein, known to bind to several different molecules, is found at higher-than-normal levels in the brains of Parkinson’s patients, and its absence or suppression in animal models was shown to protect nerve cells from damage.

Here, the researchers first found that alpha-synuclein fibrils bind strongly to RAGE. This affinity appeared to be particular for fibrils of the protein, as RAGE did not bind nearly as strongly to single alpha-synuclein molecules.

“These data indicate the strong binding between RAGE and [apha-synuclein], preferably in the form of fibrils,” the researchers wrote.

This interaction was mediated by a positively-charged domain of RAGE, which binds to a negatively-charged region of alpha-synuclein.

The team noted that this binding mechanism was similar to that previously reported between alpha-synuclein and LAG3 — another cell-surface receptor that has been implicated in the cell-to-cell transmission of alpha-synuclein fibrils.

When microglia from mice were grown in the lab with alpha-synuclein fibrils, the two strongly bonded together. In a similar experiment using microglia from mice genetically engineered to lack RAGE, the binding of alpha-synuclein to the cells was significantly diminished, but not completely abolished.

“These results indicate the essential role of RAGE in mediating the binding of [alpha-synuclein fibrils] on microglia,” the researchers wrote.

Further analyses in lab-grown mouse microglia indicated that RAGE also mediated alpha-synuclein-induced microglia activation. Microglia released significantly more pro-inflammatory molecules in the presence of alpha-synuclein clumps — indicating their activation — but not single alpha-synuclein molecules.

When RAGE was absent or suppressed in microglia, the levels of pro-inflammatory molecules were significantly reduced.

Additional analyses revealed that alpha-synuclein fibrils also could trigger the P38 phosphorylation cascade, a cell signaling pathway that leads to certain inflammatory responses in microglia. This activation was mediated, at least in part, by RAGE.

These findings suggest that “RAGE serves as a potential target for therapeutic intervention of [Parkinson’s], inhibition of which may alleviate [alpha-synuclein]-induced neuroinflammation,” the researchers wrote.

However, because blocking RAGE didn’t completely suppress the inflammatory response of microglia to alpha-synuclein clumps, there are likely other pathways at play, the team noted.

According to the researchers, future studies using animal models will be needed to further validate the study’s findings, and to explore whether RAGE works collaboratively with other microglial receptor proteins to trigger inflammation.