Summary: Study identifies AIM1 inflammasomes as crucial players in the development of a properly formed central nervous system by removing genetically compromised cells. The findings shed light on neurodevelopmental dysfunctions which occur and give rise to behavioral related disorders.
Source: University of Virginia
Improper removal of faulty brain cells during neurodevelopment may cause lifelong behavioral issues, new research from the University of Virginia School of Medicine suggests. The finding also could have important implications for a wide range of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s.
UVA neuroscientists have discovered that an unexpected form of cellular cleanup takes place in developing brains. If this process goes wrong – happening too little or too much – it can cause permanent changes in the brain’s wiring. In lab mice, this results in anxiety-like behavior, and it may play a role in neurological conditions such as autism in humans.
“You don’t want [brain] cells to have genomic compromises. You don’t want damaged DNA. So this would be a normal mechanism to expel those cells from being incorporated into the central nervous system,” explained researcher Catherine R. Lammert. “When the damage isn’t recognized, the cells that have DNA damage live on in the CNS [central nervous system] and can be seen by accumulation of DNA damage in the brain.”
Understanding Brain Development
The cellular cleaner the researchers spotted, the AIM2 inflammasome has been associated primarily with the body’s immune response to infections but has not been extensively studied in the brain. But there it plays a critical role in ensuring the developing brain is assembled properly and functions correctly, Lammert discovered in collaboration with principal investigator John Lukens, Ph.D.
“Neurodevelopment is a very complicated process,” said Lammert, a graduate student whose specialized skills were instrumental in the discovery. “This form of cell death actually plays a role in removing unwanted cells from the brain to establish a healthy CNS with the correct connections and the right number of cells.”
More than half the neurons created during brain development end up dying, so proper cleanup is essential, noted Lukens, of UVA’s Department of Neuroscience. “Too much or too little is thought to underlie everything from autism to intellectual disability – any type of neurodevelopmental disorder,” he said.
For example, ataxia is a condition that causes people to lose control of their movements. “There’s a potential that this pathway could be contributing to the neuronal loss that is seen in ataxia,” said Lukens, a researcher with UVA’s Center for Brain Immunology and Glia (BIG). “On the one hand, you need it [the cleanup] but if you have too much of it, it can have negative consequences, like, potentially, ataxia. A lot of the early-onset neurodegenerative diseases are associated with mutations in DNA damage repair proteins, and this pathway could also be involved.”
The discovery came about somewhat serendipitously, the result of an observation of the behavior of lab mice while the researchers were investigating traumatic brain injury. But following that unexpected lead has given scientists a better understanding of brain development, and that understanding may one day yield new treatments for neurological diseases.
Lukens, a member of UVA’s Carter Immunology Center, cautioned that such treatments are likely a long way off, but he said a therapy based on the discovery might have widespread applications. “Hitting this pathway in the mature brain would likely provide a treatment strategy for any neurodegenerative disease associated with DNA damage,” he said. “And that’s all the major heavy hitters: Alzheimer’s disease, Parkinson’s, ALS.”
The researchers have published their findings in the prestigious journal Nature. The study’s authors were Lammert, Elizabeth L. Frost, Calli E. Bellinger, Ashley C. Bolte, Celia A. McKee, Mariah E. Hurt, Matt J. Paysour, Hannah E. Ennerfelt, and Lukens.
Funding: The research was supported by the Hartwell Foundation; Rettsyndrome.org grant 22349; the Owens Family Foundation; and Brain & Behavior Research Foundation grant 27515. Lammert was supported by a predoctoral training grant from the National Institutes of Health’s National Institute of General Medical Sciences and a Wagner Fellowship.
AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment
Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by massive cell death in which more than half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and by-products of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signaling. How the immune response to this collateral damage influences brain maturation and function remains unknown. Here we show that the AIM2 inflammasome contributes to normal brain development and that disruption of this immune sensor of genotoxic stress leads to behavioral abnormalities. During infection, activation of the AIM2 inflammasome in response to double-stranded DNA damage triggers the production of cytokines as well as a gasdermin-D-mediated form of cell death known as pyroptosis1,2,3,4. We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this sensor of DNA damage result in anxiety-related behaviors in mice. Furthermore, we show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of gasdermin-D, and not via its involvement in the production of the cytokines IL-1 and/or IL-18. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signaling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, mutations in AIM2 lead to excessive accumulation of DNA damage in neurons as well as an increase in the number of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a crucial player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.