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Microglia Form Networks That Engulf and Clear Pathogenic α-Synuclein

The immune cells of the central nervous system, known as microglia, recognize misfolded proteins in the brain. Now, scientists have uncovered how microglia deal with the presence of α-synuclein (α-syn) fibrils. They found that microglia exposed to α-syn establish a network of intercellular connections which transfer α-syn from overloaded microglia to neighboring naive microglia. In turn, the α-syn is rapidly and effectively degraded, the α-syn burden is lowered, the inflammatory profile of microglia is attenuated, and survival is improved.

The research was published in Cell in the paper, ”Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes.

The protein α-syn performs important tasks in the nerve cells of the brain. But α-syn molecules form insoluble aggregates under certain circumstances. Indeed, several synucleinopathies including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are characterized by the presence of Lewy bodies (LB)—inclusions that are rich in an aggregated form of the protein α-syn.

Microglia try to break down and dispose of the α-syn aggregates. This process is not only time-consuming; it can also cause the microglial cells themselves to perish. “We have now identified a mechanism that addresses both problems,” explained Michael Heneka, PhD, director of the department of neurodegenerative diseases and geriatric psychiatry at the University Hospital Bonn.

The research suggests that microglial cells spontaneously join together in order to better cope with threats. For this purpose, they form tube-like projections—F-actin-dependent intercellular connections—that dock onto neighboring microglial cells. These connections are then used to distribute the α-syn aggregates among the partners in the network. Without this division of labor, individual immune cells would have to shoulder a major part of the degradation work and would be overwhelmed.

Joining forces prevents that from happening. However, the connecting tubes also serve another purpose. “They then send mitochondria to neighboring cells that are busy breaking down the aggregates,” explained Hannah Scheiblich, PhD, a postdoc at University Hospital Bonn and leading author on the paper. “Mitochondria function like little power plants; so they provide extra energy to the stressed cells.”

In certain mutations, which are found more frequently in PD patients, both α-syn and mitochondrial transport are impaired. A similar situation applies to Lewy body dementia. Researchers have isolated macrophages from blood samples of affected individuals which can be converted into microglia-like cells. “These were still able to form networks in the lab. However, the transport of α-syn through the connecting tubes was severely impaired,” said Heneka.

The fact that microglial cells can join together was previously unknown. “We have opened the door to a field that will certainly engage researchers for many years to come,” Heneka emphasized. This may also open up new therapeutic perspectives for neurological disorders such as PD or dementia.

Graphical abstract Scheiblich et al.

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