EVs released from microglia may aid Sanfilippo neurodegeneration
Study: Cells exposed to patients' sugar molecules were more inflammatory
The release of extracellular vesicles (EVs) from microglia may play a key role in driving neurodegeneration in Sanfilippo syndrome.
EVs are tiny particles that carry a variety of cargo, such as proteins and DNA, between cells to facilitate cell-to-cell communication. Microglia are a class of immune cells in the brain.
When the cells were exposed in the lab to sugar molecules from the urine of Sanfilippo patients, which are the known driver of the disease, they released EVs with cargo that seemed to promote inflammation and inhibit neurodevelopment. In turn, the EVs caused nerve cells (neurons) to lose the projections that are critical for proper brain signaling.
“Our results strongly suggest that in patients with [Sanfilippo], microglia-derived EVs accentuate inflammation and neuronal dysfunction,” the researchers wrote. “This work provides a framework for further studies of biomarkers to evaluate efficiency of emerging therapies.”
The study, “Extracellular vesicles from microglial cells activated by abnormal heparan sulfate oligosaccharides from Sanfilippo patients impair neuronal dendritic arborization,” was published in Molecular Medicine.
In Sanfilippo syndrome, or mucopolysaccharidosis type 3, a large sugar molecule called heparan sulfate can’t be broken down properly in cells due to genetic mutations that lead to a deficiency in the enzymes needed to do it.
Partially degraded heparan sulfate fragments accumulate to toxic levels and cause tissue damage, especially in the brain. This leads to a pediatric form of dementia that’s characterized by developmental delays and behavioral issues, among other symptoms.
Sanfilippo immune cells more inflammatory
There’s substantial overlap between Sanfilippo and adult neurodegenerative diseases, including the presence of neuroinflammation. Evidence indicates microglia, the brain’s resident immune cells, are key players in driving neuroinflammation and subsequent cell death across neurodegenerative diseases.
EVs are released from cells and taken up by others as a means of communication, and their cargo can influence the behavior of the recipient cell. EVs released from microglia might play an important role in spreading neurodegeneration, but their exact role in Sanfilippo hasn’t been explored.
Here, scientists profiled microglial EVs from a cell model of Sanfilippo. To generate the model, mouse microglia were incubated in the lab with glycosaminoglycans (GAGs), a class of sugar molecule that includes heparan sulfate, that were extracted from the urine of Sanfilippo patients or healthy children. Microglia exposed to GAGs from Sanfilippo patients took on a more inflammatory profile than those exposed to GAGs from the children who were healthy.
EVs released from the microglia were then collected and analyzed. A number of proteins were at altered levels in the Sanfilippo EVs compared with the healthy ones, results showed.
Proteins that were more abundant in the Sanfilippo EVs were often related to inflammatory responses and immune cell metabolism or recruitment. Less abundant ones tended to be related to neurodevelopment.
There were also differences in the EV content of microRNA (miRNA), which are molecules involved in regulating gene activity. Altered miRNAs appeared to regulate similar biological pathways as those found to be affected in the protein analyses.
To learn more about how nerve cells respond to different EV cargo, the scientists incubated mouse neurons with the isolated healthy or Sanfilippo EVs.
The neurons exposed to Sanfilippo EVs had fewer nerve cell projections than those exposed to healthy EVs. They also had fewer and shorter dendrites, which are the branches that extend from nerve cells that receive signals from other cells, and more dendrites seemed to be in an immature state. The scientists suggested this could mean the cells won’t form as many connections with other nerve cells, which is critical for proper brain function.
The bodies of the Sanfilippo EV-exposed neurons also appeared swollen, a known feature of neurodegeneration.
“This study shows, for the first time, that GAGs from patients with Sanfilippo syndrome can induce microglial secretion of EVs that deliver a specific molecular message to recipient … neurons, while promoting the neuroinflammation, and depriving neurons of neurodevelopmental factors,” the researchers wrote.
In other neurodegenerative diseases, evidence suggests EVs may contribute to cell dysfunction and death by transporting abnormal or toxic proteins between cells. Whether EVs in Sanfilippo are carrying heparan sulfate fragments between nerve cells to drive neurodegeneration remains to be determined, the researchers said.
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