Rett syndrome is a devastating neurological disorder, almost exclusively affecting girls. Rett is predominantly caused by mutations in an X-linked gene encoding methyl-CpG-binding protein (MECP)2. Until recently, the etiology of the disease was assumed to be purely neuronal. However, the role of glia in the pathology of Rett syndrome (and of other CNS diseases) has now been recognized. Expression of wild type Mecp2 in astrocytes of Mecp2-null hosts has been shown to dramatically ameliorate disease pathology. Microglia were also recently suggested to play a role in Rett pathophysiology;Mecp2-null microglia were reported to be toxic to neurons through production of high levels of glutamate. Along these lines, it is generally well accepted by now that non-neuronal cells of the CNS are critically important for brain function. Our preliminary data that serves as a basis for this proposal, demonstrates the unique role myeloid cells play in arrest of Rett pathology. 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 Lysmcre on an Mecp2-null background, dramatically attenuated disease symptoms. In irradiated mice, newly- engrafted brain mononuclear phagocytes produced high levels of insulin-like growth factor 1 (IGF-1), unlike resident mutant microglia, possibly one underlying molecular mechanism of rescue. Interestingly, however, inhibition of phagocytic activity using annexin V that blocks phosphatydilserine residues on apoptotic targets and prevents their recognition and engulfment by tissue-resident phagocytes, abolished disease arrest. Based on our preliminary results, we hypothesize that Mecp2-null microglia are incapable of providing neurotrophic support and are insufficient to the task of debris clearance (including synaptic pruning, elimination of dead cells etc.), thus contributing to the ongoing pathophysiology seen in Rett syndrome. Our data implicate microglia as major players in Rett pathophysiology, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for this devastating disorder. However, a further understanding of the role played by microglia in disease pathology and repair on a molecular level is crucial for efficient translation of these studies to clinic. This proposal is aimed to study the underlying mechanism of microglia-mediated arrest of Rett pathology by (1) establishing the role of microglia in Rett pathology and repair using genetic and pharmacological approaches;(2) addressing the relative contribution of peripheral immune-derived IGF-1 and microglia-derived IGF-1 in arrest of Rett disease, using bone marrow transplantation and genetic crosses;and (3) testing the hypothesis that the deficiency in phagocytic clearance by microglia may underlie, in part, the pathophysiology of Rett using mice deficient in macrophage phagocytic activity as bone marrow donors.
Rett syndrome is a devastating neurological disorder, almost exclusively affecting girls. Rett is predominantly caused by mutations in an X-linked gene encoding methyl-CpG- binding protein (MeCP)2. Until recently, the etiology of the disease was assumed to be purely neuronal. However, the role of glia in the pathology of Rett syndrome has now been recognized. Our results show that bone marrow transplantation into mouse model of Rett disease (Mecp2-null mice) arrests disease progression. Bone marrow transplantation could, therefore, be developed into a promising therapeutic approach for Rett disorder but an underlying mechanism needs to be better understood. This grant is aimed to understand the role played by myeloid cells in Rett arrest after bone marrow transplantation or expression of wild type Mecp2 in myeloid cells.
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|Derecki, Noel C; Cronk, James C; Kipnis, Jonathan (2013) The role of microglia in brain maintenance: implications for Rett syndrome. Trends Immunol 34:144-50|
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