#alpha-synuclein
Immune cells in the brain share the work
To break down toxic proteins more quickly, immune cells in the brain can join together to form networks when needed. This is shown by a joint study of the University of Bonn, the German Center for Neurodegenerative Diseases (DZNE) and the Institut François Jacob in France. However, in certain mutations that can cause Parkinson’s disease, this cooperation is impaired. The findings are published in the renowned journal Cell.
The protein alpha-synuclein (abbreviated aSyn) performs important tasks in the nerve cells of the brain. But under certain circumstances, 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 perish. “We have now identified a mechanism that addresses both problems,” explains Prof. Dr. Michael Heneka. The researcher is director of the Department of Neurodegenerative Diseases and Geriatric Psychiatry at the University Hospital Bonn and conducts research there and at the DNZE on neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease.
Division of labor prevents overload
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,” explains Heneka’s colleague Dr. Hannah Scheiblich. “Mitochondria function like little power plants; so they provide extra energy to the stressed cells.”
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,” says Heneka, who is also a member of the Cluster of Excellence ImmunoSensation2 and the transdisciplinary research area “Life & Health”.
Findings may open up new therapeutic perspectives
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 emphasizes. In the medium term, this may also open up new therapeutic perspectives for neurological disorders such as Parkinson’s disease or dementia.
(Image caption: Microglial cells - (blue: the cell nuclei) can join together using tubular projections (red) to degrade dangerous proteins in a division of labor. Credit: © AG Heneka/University of Bonn)
How a Parkinson’s disease-linked protein attacks a cell’s powerhouses
Inside cells, organelles called mitochondria carry out a medley of vital tasks. These structures generate energy and help to keep the cells’ interior environment in a state of healthy equilibrium, among other functions.
Now, scientists show how a protein associated with Parkinson’s disease can damage these cellular powerhouses.
The findings come from experiments in which fruit fly larvae were genetically engineered to produce unusually high amounts of the protein, called alpha-synuclein.
“When fruit fly larvae expressed alpha-synuclein at elevated levels similar to what is seen in Parkinson’s disease, many of the mitochondria we observed became unhealthy, and many became fragmented. Through detailed experiments, we also showed that different parts of the alpha-synuclein protein seem to be responsible for these two problems, and that fragmented mitochondria can actually be healthy. This is a key finding, because before, people thought fragmented mitochondria were unhealthy mitochondria,” says Shermali Gunawardena, PhD, associate professor of biological sciences in the University at Buffalo College of Arts and Sciences.
The results could be of interest in the context of drug development, as abnormal aggregates of alpha-synuclein in brain cells are a hallmark of Parkinson’s disease, and mitochondrial damage has also been observed in patients.
“This research showcases the advantage of using fruit fly larvae as a model organism to study how neurons become damaged during devastating diseases such as Parkinson’s disease,” says TJ Krzystek, UB PhD candidate in biological sciences. “Through this approach, we pieced together a new understanding for how the Parkinson’s disease-related protein alpha-synuclein disrupts the health and movement of mitochondria — the epicenter for energy production in cells. We believe this work emphasizes a promising path that can be explored for potential therapeutics aimed at improving mitochondrial health in Parkinson’s disease patients.”
The study was published in the journal Cell Death and Disease.
The co-first authors are Krzystek and Rupkatha Banerjee, PhD, a postdoctoral research associate at Scripps Research who completed her doctorate in biological sciences at UB. Gunawardena is the senior author.
The research was a collaborative effort, with many members of the Gunawardena lab making significant contributions. In addition to Banerjee, Gunawardena and Krzystek, the paper’s authors include undergraduates Layne Thurston, JianQiao Huang and Saad Navid Rahman, and PhD student Kelsey Swinter, all in the UB Department of Biological Sciences, and Tomas L. Falzone at the Universidad de Buenos Aires and Instituto de Investigación en Biomedicina de Buenos Aires.
A detailed look at alpha-synuclein and mitochondria
Through tests in fruit fly larvae, the scientists were able to tease out intricate details regarding interactions between alpha-synuclein and mitochondria.
For example, the study not only concludes that different sections of the alpha-synuclein protein are likely responsible for causing mitochondrial fragmentation and damaging mitochondrial health; the research also identifies these sections and describes how other proteins may interact with them to drive these changes. More specifically, the proteins PINK1 and Parkin — both linked to Parkinson’s disease — may interact with one end of alpha-synuclein to influence mitochondrial health, while a protein called DRP1 may interact with the other end to break mitochondria, scientists say.
“Mitochondrial impairments have long been linked to the pathogenesis of Parkinson’s disease,” Banerjee says. “However, the role of alpha-synuclein in mitochondrial quality control so far has not been comprehensively investigated. Our study unravels the intricate molecular mechanisms by which the different regions of alpha-synuclein exert distinct effects on mitochondrial health, bringing into light a potential pathway that could be targeted for exploring new therapeutic interventions in Parkinson’s disease.”
“We were able to tease out specific mechanistic functions for alpha synuclein by using imaging tools and a color-tagged marking system to observe the process of what happens to mitochondria when alpha-synuclein is elevated,” Gunawardena adds. “This system allowed us to observe the health, size and the movement behaviors of mitochondria at the same time in living neurons in a whole organism.”
(Image caption: Unhealthy mitochondria are marked in a gradient from white to red, with white being the least healthy, in contrast to healthy mitochondria that appear in blue. This still image is from a microscope video showing mitochondria moving in a fruit fly larval neuron expressing elevated levels of the protein alpha-synuclein. Credit: TJ Krzystek and Shermali Gunawardena)
