To break down toxic proteins faster, immune cells in the brain can come together to form networks when needed. This is shown by a joint study by the University of Bonn, the German Center for Neurodegenerative Diseases (DZNE) and the François Jacob Institute in France. However, in some mutations that can cause Parkinson’s disease, this cooperation is impaired. The results are published in the famous journal Cell.
The alpha-synuclein protein (abbreviated as aSyn) performs important tasks in nerve cells in the brain. But under certain circumstances, aSyn molecules can clump together and form insoluble aggregates. These damage neurons; they are, for example, typically found in the brains of people suffering from Parkinson’s disease or Lewy body dementia.
The brain’s immune cells, the microglial cells, therefore try to break down and eliminate the aSyn aggregates. This process doesn’t just take time; it can also kill the microglial cells themselves. “We have now identified a mechanism that solves both problems,” says Professor Michael Heneka. The researcher is Director of the Department of Neurodegenerative Diseases and Geriatric Psychiatry at Bonn University Hospital and conducts research there and at the DNZE on neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease.
Division of labor avoids overload
Research suggests that microglial cells can join together spontaneously in order to better cope with threats. To this end, they form tube-shaped projections that attach to nearby microglial cells. These connections are then used to distribute the aSyn aggregates among the network partners. Without this division of labor, individual immune cells would have to do much of the breaking down work and be overwhelmed.
Joining forces prevents this from happening. However, the connecting tubes also serve another purpose – microglial cells can use them to give their neighbors a boost when they are in too much distress, or even in danger of death. “They then send mitochondria to neighboring cells which are busy breaking down the aggregates,” explains Heneka’s colleague Dr Hannah Scheiblich. “Mitochondria work like little power plants; they therefore provide additional energy to stressed cells. “
In some mutations, which are more commonly found in patients with Parkinson’s disease, aSyn and mitochondrial transport is impaired. A similar situation applies to another disease in which the breakdown of aSyn is impaired: Lewy body dementia. Researchers isolated certain immune cells, macrophages, from blood samples of affected individuals. These can be converted into microglia-like cells using specific regulatory molecules. “These were still able to form networks in the laboratory. However, the transport of aSyn through the connecting tubes was severely disrupted, ”explains Heneka, who is also a member of the Immunosensation2 cluster of excellence and the“ Life & Health ”transdisciplinary research area.
The results may open up new therapeutic perspectives
Whether microglial cells can join together was previously unknown. “We have opened the door to an area that will certainly engage researchers for many years to come,” says Heneka. In the medium term, this may also open up new therapeutic perspectives for neurological disorders such as Parkinson’s disease or dementia.
Scheiblich, H., et al. (2021) Microglia jointly degrade the fibrillary cargo of alpha-synuclein by distribution through tunnel nanotubes. Cell. doi.org/10.1016/j.cell.2021.09.007.