development disorder, epigenetics, genetics, healthinnovations, immune response, immune system, immunology, inflammation, MeCP2 gene, neurodevelopment, neurogenetics, neuroinflammation, Rett syndrome

Researchers identify the role of microglia in Rett syndrome.

New research by researchers at the University of Massachusetts suggests the immune system plays an unsuspected and surprising role in the progression of Rett syndrome, a severe neurological disorder affecting children. The development disorders is marked by immune cells known as macrophages being unable to perform their normal function, instead amplifying the disease. The data findings point to the immune system as a promising target for slowing the progression of Rett syndrome.  The opensource study is published in the journal Immunity.

The team state that Rett syndrome patients have a mutation that makes macrophages hyper-sensitive to specific stress signals. This means that this part of the immune system is constantly on. This causes damage to the surrounding tissue and eventually wears out the macrophages which die off en masse.  This data findings point to the immune system as an important contributor to the disease. The team hypothesize that if they can find a way to modulate the immune system, it’s possible they could delay the progression of symptoms in patients.

The researchers explain that Rett syndrome is a neurodevelopmental disorder that is caused primarily by mutations in the gene encoding for MeCP2, an important epigenetic regulator. In the brain, MeCP2 is found in high concentrations in neurons and is associated with maturation of the central nervous system and the formation of synaptic connections. Children with the disorder appear to develop normally but begin to lose acquired cognitive and motor skills at 6 to 18 months of age as symptoms start to show. As they age, patients are unable to acquire verbal skills and suffer from lack of motor control.

Though the hallmark of Rett syndrome is neurological, related symptoms include gastrointestinal and digestive issues that can lead to poor weight gain and nutritional problems, as well as heart, bone and muscle complications. Previous studies indicated that microglia, a type of macrophage found in the brain, may have a role in the disease.  The researchers state that knowing that microglia play an important role in the pathogenesis of Rett syndrome played an important part in the theory that other types of macrophages might be contributing to the disease as well.

What the current study found was that the MeCP2 gene is responsible for establishing a threshold for the activation of macrophages in the presence of stimuli and stressors such as hypoxia, corticosteroids and inflammation. During the course of a normal day, macrophages encounter varying levels of these stimuli. In cells with the MeCP2 mutations, the macrophages are far more sensitive and respond to much lower levels of stimuli and stress. This activation causes additional stress which keeps the macrophages turned on in a cycle that amplifies and further damages the cells and surrounding tissues. Thus the results show that it’s likely this damage is contributing to the progression of the disease and onset of symptoms.

The team surmise that previous studies have shown how to modulate the immune system. And with a bone marrow transplant researchers can even replace a person’s entire immune system. However, they conclude that at this stage it’s unlikely that the team could cure Rett syndrome without addressing the MeCP2 in neurons, but this study provides evidence that by addressing the disease in the immune system the medical community could potentially delay the onset of symptoms.

Source:  University of Massachusetts Medical 

 

Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1creER increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome. Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli. Kipnis et al 2015.
Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1creER increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome. Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli. Kipnis et al 2015.

 

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