Effect of the inhibition of the Wiskott-Aldrich syndrome protein in the functions of microglia during neurodevelopment

The Wiskott-Aldrich syndrome (WAS) is a rare disease caused by WAS mutations, leading to immunodeficiency. In 40% of WAS patients neurological complications are reported. We propose that neurological deficits are partly due to impaired myeloid-cell-mediated brain development and homeostasis. The WAS protein (WASp) is indeed expressed by microglia, key cells for neurodevelopment and neuroinflammation. To define WASp’s role in brain, we inhibited the protein pharmacologically in microglia derived from human-induced pluripotent stem cells or in zebrafish embryos. In presence of WASp inhibitors (Wiskostatin, CK-666), microglia: 1) reduced phagocytic activity and changed motility (by time-lapse confocal); reduced cytoskeletal filopodia (by fixed cell immunofluorescence). Zebrafish embryos with CK-666 had slower response to stimulation and accumulation of brain apoptotic bodies. These findings suggest that microglia dysfunction contributes to WAS-related neurological symptoms.