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Mass E, Jacome-Galarza CE, Blank T, Lazarov T, Durham BH, Ozkaya N, Pastore A, Schwabenland M, Chung YR, Rosenblum MK, Prinz M, Abdel-Wahab O, Geissmann F. A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature. 2017 Aug 30; PubMed.
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University of Freiburg
The authors very elegantly modeled the etiology and progression of neurodegeneration in patients with histiocytoses in a mouse model with mosaic somatic expression of the BRAF V600E mutation in yolk sac-derived erythro-myeloid progenitors (EMPs). Within the CNS, a key consequence of targeting a subset of EMPs in this way was to give rise to a small population of ERK-activated microglia. Microglial cells that carry the BRAF mutation were conferred survival and proliferative advantages, possibly as a result of the hyperactive RAS-MEK-ERK signaling. What I found interesting was that normal microglia, which presumably inhabited the bulk of the CNS, were unable to promote homeostasis in the long run by out-proliferating the rogue microglial cells just on the basis of being the healthy majority. Evidently, the steady state self-renewal rates of microglia (Askew et al., 2017; Tay et al., 2017) are insufficient to overcome dysfunctional microglia with perturbed cell cycling.
This study brought to mind the Nasu-Hakola disease (NHD) that is caused by inherited mutations in either the TREM2 or TYROBP genes, which in the CNS are mainly expressed in microglial cells. A feature of NHD is early onset dementia in patients who typically do not survive beyond 50 years of age. Here, Mass et al. showed that neurodegeneration indicated by gliosis, accumulation of amyloid precursor protein, degradation of myelin, and neuronal death has a late onset. Given the authors found constitutive expression of BRAF V600E in EMPs resulted in embryonic lethality, it is possible that the somatic mutation has a dosage effect. Remarkably, the presence of BRAF V600E microglia in this mouse model appeared to have little impact in early postnatal brain development. Symptoms that presented later in middle-aged adults were mainly neurologic.
The BRAF inhibitor was reportedly very effective in delaying the onset of neurological symptoms in the mouse model and in some patients with histiocytic CNS diseases. In the accompanying Nature News & Views, it was suggested that molecular targets restricted to EMPs or microglia could be identified for therapeutic benefits. However an alternative could be to explore the feasibility of host-derived bone marrow transplantation to replace some endogenous healthy and mutant microglia, since the HSC lineages are free of the mutation. Given that the pathologic brain regions were mainly the brain stem and cerebellum, the engraftment of disease-free peripheral BM-derived cells that integrate long-term as macrophages may be more permissible in these compartments.
References:
Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y, Richardson P, Tipton T, Chapman MA, Riecken K, Beccari S, Sierra A, Molnár Z, Cragg MS, Garaschuk O, Perry VH, Gomez-Nicola D. Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain. Cell Rep. 2017 Jan 10;18(2):391-405. PubMed.
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