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Nov 9
2021

Overactive Microglial Pruning linked to Defective C9orf72 Gene in Neurodegenerative Diseases

ALS Headlines, Research Bytes
Researchers identify how C9orf72 triggers inflammation and age-dependent neural defects that affect learning and memory.

Defects in the C9orf72 gene have been associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia and Alzheimer’s disease. While the gene is expressed in all brain cells, it can be found in the highest concentration in microglia, the primary immune cells of the central nervous system (CNS) that are responsible for responding to injury and removing pathogens and damaged cells. 

Rita Sattler, M.Sc., Ph.D., joined Deepti Lall, Ph.D., and Robert Baloh, M.D., Ph.D., at Cedars Sinai Medical Center to evaluate the role that C9orf72 dysfunction plays in microglial behavior through a series of in vitro and in vivo studies.Their results illustrate the link between C9orf72 dysfunction and overactive microglial synaptic pruning that may be key to learning and memory deficits. The results are available in the journal Neuron.

“Microglia are interesting,” said Sattler, professor in the Department of Translational Neuroscience at the Barrow Neurological Institute and lead author on the paper. “They are very mobile cells and migrate to the site of brain injury where they clear away debris like a vacuum cleaner, removing toxins and damaged cells that accumulate.”

Microglia are more than just the custodian department for the CNS. These cells also play an integral role in how the brain develops. In an embryo, the brain sets out a myriad of synaptic connections to develop the organ’s architecture. As we mature, the brain fine tunes this network by skillfully editing the extra spines and connections. To accomplish this task, it turns to the microglia. This was the tantalizing component of the microglia skillset that caught the team’s attention.

Through a series of RNA-sequence analyses, the team took a step-by-step approach to evaluate how the loss of C9orf72 effected microglia function. They evaluated the DNA of the microglia isolated from the C9orf72 knock-out mice and found dysregulation in the inflammatory response that prompts the microglia to go out on cleaning missions. They next evaluated knock-out mice where C9orf72 was only removed from the microglia rather than all of the brain cells and found similar results. The in vitro model of microglial cells mirrored the phenomenon seen in the in vivo system, suggesting a cell autonomous event.

Sattler explains that the C9orf72-deficient microglia go into overdrive with two tasks — overactive synaptic pruning as well as toxic plaque clearance. It may seem counter-intuitive, but the enhanced clearing of amyloid plaques did not improve the behavior or learning in the mice. Instead, the animals experienced more severe learning and memory deficiencies. 

“The most exciting part of this study was the amyloid surprise,” said Sattler. “We did not expect to see less amyloid but increased behavioral deficiency.”

To Sattler, this result suggests that the real culprit to changes in learning and behavior, which characterizes Alzheimer’s disease, frontotemporal dementia and some ALS patients, is overactive pruning of synapses.

Sattler believes the results from this study provide an opportunity for researchers to test therapeutic approaches for familial and sporadic ALS. While it is not possible to study sporadic ALS (sALS) in animal models, there is an opportunity to look for pathways in induced pluripotent stem cells (iPSCs) obtained from sALS patients. She believes an analogous pathway may produce similar outcomes to the knock-out C9orf72 findings.

“Anything we learn from familial cases, which are easier to model, could be translated to sporadic ALS,” said Sattler. “We are currently developing human-derived iPSC microglial cells to better understand the cross talk between microglia and neurons using patient-derived model systems.”

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Sattler joined a team of colleagues at six institutions on the project titled, “C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation.” This project received funding from the National Institutes of Health, the Robert and Louise Schwab family, the Cedars-Sinai ALS Research Fund, the JPB Foundation, the Muscular Dystrophy Association, the ALS Association, the Robert Packard Center for ALS Research, the Barrow Neurological Foundation, the Rainwater Charitable Foundation and the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program.

~Stacy Kish