Developmental Biology - Neurologic Development|
AIM2 a Source of Lifelong Behavioral Issues?
New finding could have important implications for neurodegenerative disease therapy...
New research from the University of Virginia School of Medicine (UVA) indicates that improper removal of faulty brain cells during early neurodevelopment may cause lifelong behavioral issues. The finding could have important implications for neurodegenerative diseases such as Alzheimer's and Parkinson's.
AIM2 inflammasome scans for DNA damage,
which shapes neurodevelopment.
The research published in the journal Nature, reveals UVA neuroscientists found an unexpected form of cellular cleanup taking place in developing brains. If the process goes wrong - too little or too much - permanent changes to the brain's wiring can occur. In lab mice, anxiety-like behavior results in affected mouse models. In humans, DNA damage failing to be "cleaned up" may play a role in neurological conditions such as autism.
"You don't want damaged DNA. There is a normal mechanism to expel cells from being incorporated. When damage isn't recognized and expelled, damaged cells accumulate and live on in the CNS."
Catherine R. Lammert PhD, Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Understanding Brain Development
The cellular cleaner AIM2 inflammasome, is associated primarily with the body's immune response to infections, which hasn't been extensively studied in the brain. Now, Lammert in collaboration with principal investigator John Lukens PhD, researcher with the Center for Brain Immunology and Glia (BIG) in UVA's Department of Neuroscience, together discovered AIM2 inflammasome is critical to brain development in supporting proper clean up.
"Neurodevelopment is a very complicated process. 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. Too much or too little is thought to underlie everything from autism to intellectual disability - or any type of neurodevelopmental disorder."
John Lukens PhD, Neuroscience Graduate Program, and project Principal Investigator, School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
More than half the neurons created during brain development end up dying, so proper cleanup is essential, notes Lukens.
For example, ataxia is a condition causing people to lose control of their movements. "There's a possibility this pathway could be contributing to the neuronal loss seen in ataxia," explains Lukens. "On the one hand, you need it [the cleanup] but if you have too much of it, it can have negative consequences, like ataxia. A lot of 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. Following that unanticipated lead has given scientists a better understanding of brain development — and may one day yield new treatments for neurological diseases.
Lukens cautions that such treatments are likely a long way off. But adds that a therapy based on this discovery might have widespread applications...
"... this pathway in a mature brain would likely provide a treatment strategy for any neurodegenerative disease associated with DNA damage. This would be true for Alzheimer's, Parkinson's and ALS."
John R. Lukens PhD.
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 signalling. 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 behavioural 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 behaviours 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 signalling 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.
Catherine R. Lammert, Elizabeth L. Frost, Calli E. Bellinger, Ashley C. Bolte, Celia A. McKee, Mariah E. Hurt, Matt J. Paysour, Hannah E. Ennerfelt and John R. Lukens.
The authors thank members of the Lukens laboratory and the Center for Brain Immunology and Glia (BIG) for discussions. This work was supported by The Hartwell Foundation (Individual Biomedical Research Award to J.R.L.), a Rettsyndrome.org grant (22349 to J.R.L.), The Owens Family Foundation (awarded to J.R.L.), and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (27515 to J.R.L.). C.R.L was supported by a NIH National Institute of General Medical Sciences predoctoral training grant (3T32GM008328) and a Wagner Fellowship. A.C.B. was supported by a Medical Scientist Training Program Grant (5T32GM007267-38) and an Immunology Training Grant (5T32AI007496-25). H.E.E. was supported by a Cell and Molecular Biology Training Grant (T32GM008136). E.L.F. was supported by a National Multiple Sclerosis Foundation Postdoctoral Fellowship (FG-1707-28590). C.E.B. was supported by Hutcheson and Stull Undergraduate Research Fellowships.
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Apr 16 2020 Fetal Timeline Maternal Timeline News
Lack of AIM2 inflammasome components increase Purkinje neurons incorporated into adult mouse brains. Images of cerebellums from adult mice (8–12 weeks old) wild (normal) type, Ice-/-, Aim2-/- and Gsdmd-/- mice show an increase in Purkinje cells (calbindin? cells) in mice lacking inflammasome components. CREDIT UVA Communications. Access Via Research Gate.