Microglia, the brain’s immune cells, may go awry in FA: Mouse study
Understanding cells' behavior could lead to strategies to stop neurodegeneration
Microglia, the brain’s resident immune cells, may go awry in Friedreich’s ataxia (FA) and contribute to lasting inflammation in the brain, possibly playing a part in nerve cell degeneration, according to a new study in a mouse model of the disease.
“This work is the first to provide multilayer evidence [including] metabolic analysis … that [Friedreich’s ataxia] microglia are dysfunctional,” the researchers wrote.
Understanding how microglia behave could lead to new approaches to stop neurodegeneration or repair damaged neurons in FA, the team noted.
The study, “Loss of homeostatic functions in microglia from a murine model of Friedreich’s ataxia,” was published as a rapid communication in the journal Genes & Diseases.
Differences in shape of microglia cells seen in FA mouse model
Friedreich’s ataxia is a neurodegenerative disease caused by mutations in the FXN gene, which provides instructions for making a protein called frataxin. This protein is needed for the healthy functioning of mitochondria, the energy-producing structures of cells.
When frataxin is faulty or missing, iron may build up in mitochondria, which then may not be able to produce enough energy to supply cells in the brain, spinal cord, and muscles. All can thus become damaged, leading to symptoms of Friedreich’s ataxia.
Microglia are highly mobile immune cells with an array of functions that contribute to the development of the brain and spinal cord, and help maintain a healthy balance in these tissues.
These functions include processes such as phagocytosis, in which microglia engulf and consume either tissue debris — to maintain tissue balance, resolve inflammation, and promote tissue repair — or synapses, to remodel neuron circuits. Synapses are the point of near contact between neurons where they release chemical and electrical signals to communicate.
Increasing evidence suggests that chronic microglia activation in response to injury in neurodegenerative diseases can lead to sustained neuroinflammation and, ultimately, to further neuron damage.
Earlier work has shown that microglia also may become overly active in the brain of people with FA, with more active microglia linked to earlier symptom onset.
To better understand the role of microglia, a team of researchers in Italy now turned to a mouse model of FA .
The researchers first confirmed that these mice had lower levels of frataxin than did healthy mice. But they also found that the number of microglia present in the brain was about the same.
When examined under a microscope, however, microglia from model mice looked different from healthy ones, with more irregular edges and an elongated shape with a larger diameter.
These differences in shape were related to abnormal functions, as microglia from mice with FA-like disease moved significantly less, but were more phagocytic.
In the presence of an iron chelator, which reduces iron overload, mobility and phagocytosis were partially rescued, “suggesting that disturbed iron regulation, resulting from frataxin deficiency, could contribute to the observed changes in microglial [profiles],” the team wrote.
Study show microglia plays a role in neuron degeneration in FA
When the team looked at microglia’s gene activity, the researchers found significant differences in 184 genes between model and healthy mice. About half showed significantly higher activity, while the other half showed significantly lower activity.
The top 10 genes with significantly different activity provided instructions for molecules involved in mitochondria’s energy production processes, inflammation, and the dynamic regulation of a balanced, working set of proteins in cells.
These findings suggested that microglia from mice with FA-like disease “exhibit altered [shape], proinflammatory features, and dysfunctional mitochondria,” the researchers wrote.
Further analyses showed that microglia from model mice produced significantly more pro-inflammatory molecules and showed alterations in mitochondrial function, with decreased oxygen consumption and increased glycolysis. Glycolysis is a series of reactions that allow cells to produce small amounts of energy in the absence of oxygen.
“These alterations are typical of reactive microglia and are generally associated with a cytotoxic [cell-killing] function,” the researchers wrote.
These results provide evidence that microglia can participate in neuron degeneration in [Friedreich’s ataxia].
When healthy mouse neurons were grown in the lab in the presence of molecules secreted by microglia from model mice, they grew fewer and shorter neurites, a type of projection used to relay messages from one neuron to the next. They also did not survive as long as those grown in the presence of molecules secreted by healthy microglia.
“These results provide evidence that microglia can participate in neuron degeneration in [FA],” the researchers wrote.
In addition, analysis of brain tissue from young model mice at an early phase of the disease revealed changes in microglia shape as well as low levels of “key microglial molecules mediating the process of synapse refinement during neurodevelopment,” the team wrote.
These findings suggest that microglia may go awry in FA, possibly contributing to the disease, according to the researchers.
The team concluded that understanding FA’s underlying microglia-related mechanisms “could be instrumental in designing time- and molecule-targeted therapeutic interventions.”
The research was funded by grants from the National Ataxia Foundation and the Friedreich’s Ataxia Research Alliance.
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