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Wild-type microglia arrest pathology in a mouse model of Rett syndrome
Noël C Derecki1, James C Cronk, Zhenjie Lu
1Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
Abstract:
Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.
Insights
Microglia play a crucial role in Rett syndrome, an X-linked disorder. Replacing defective cells with healthy microglia via bone marrow transplantation can significantly improve disease symptoms and lifespan in mouse models.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Rett syndrome is an X-linked disorder often linked to MECP2 gene mutations.
- While neuronal dysfunction is primary, astrocytes and now microglia are implicated in Rett pathophysiology.
- Microglia, the brain's immune cells, were investigated for their role in Rett syndrome.
Purpose of the Study:
- To investigate the role of microglia in Rett syndrome pathogenesis.
- To determine if bone marrow transplantation (BMT) and microglial engraftment can ameliorate Rett syndrome symptoms.
- To explore the therapeutic potential of targeting microglia in Rett syndrome.
Main Methods:
- Bone marrow transplantation from wild-type to Mecp2-null mice.
- Blocking cranial irradiation to prevent microglial engraftment.
- Targeted expression of MECP2 in myeloid cells using Lysm(cre) mice.
- Pharmacological inhibition of microglial phagocytic activity.
Main Results:
- BMT led to microglial engraftment and arrested disease development in Mecp2-null mice.
- Preventing microglial engraftment halted disease arrest, while targeted MECP2 expression in myeloid cells attenuated symptoms.
- Wild-type microglia significantly improved lifespan, breathing, body weight, and locomotor activity in affected mice.
- Microglial phagocytic activity was essential for mediating these therapeutic benefits.
Conclusions:
- Microglia are critical players in Rett syndrome pathophysiology.
- Bone marrow transplantation offers a potential therapeutic strategy for Rett syndrome.
- Microglial phagocytosis is a key mechanism underlying the therapeutic effects observed.
