To degrade toxic proteins more rapidly, immune cells in the brain can join together to form networks when needed, a joint study of the University of Bonn, the German Center for Neurodegenerative Diseases (DZNE) and the Institut François Jacob in France shows1. However, in certain mutations that can cause Parkinson’s disease, this cooperation is impaired.
The protein alpha-synuclein performs important tasks in the nerve cells of the brain. But under certain circumstances, alpha-synuclein (aSyn) molecules can clump together and form insoluble aggregates. These damage the neurons; they are for instance typically found in the brains of people suffering from Parkinson’s disease or Lewy body dementia.
The immune cells of the brain, the microglial cells, therefore try to break down and dispose of the aSyn aggregates. This process is not only time-consuming; it can also cause the microglial cells themselves to perish2.
We have now identified a mechanism that addresses both problems,
said Prof. Dr. Michael Heneka, director of the Department of Neurodegenerative Diseases and Geriatric Psychiatry at the University Hospital Bonn.
Division Of Labor
The research suggests that microglial cells may spontaneously join together in order to better cope with threats. For this purpose, they form tube-like projections that dock onto neighboring microglial cells.
These connections are then used to distribute the aSyn 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: Microglial cells can use them to give their neighbors a boost when they are in too much distress or indeed in mortal danger.
They then send mitochondria to neighboring cells that are busy breaking down the aggregates. Mitochondria function like little power plants, so they provide extra energy to the stressed cells,
explained Dr. Hannah Scheiblich.
Lewy Body Dementia
In certain mutations, which are found more frequently in Parkinson’s disease patients, both aSyn and mitochondrial transport are impaired. A similar situation applies to another disease in which the degradation of aSyn is impaired: Lewy body dementia.
Researchers have isolated certain immune cells, the macrophages, from blood samples of affected individuals. These can be converted into microglia-like cells with the help of specific regulatory molecules.
These were still able to form networks in the lab. However, the transport of aSyn 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. In the medium term, this may also open up new therapeutic perspectives for neurological disorders such as Parkinson’s disease or dementia.
The work was supported by funding from the Joint Program on Neurodegenerative Diseases, the Gemeinnützige Hertie Stiftung, National Institutes of Health, and German Research Foundation.
Hannah Scheiblich et al. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes Cell (2021). DOI: 10.1016/j.cell.2021.09.007 ↩︎