DOCK8 is expressed in microglia, and it regulates microglial activity during neurodegeneration in murine disease models
Year: 2019
Type: article
Abstract: Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor whose loss of function results in immunodeficiency, but its role in the central nervous system (CNS) has been unclear. Microglia are the resident immune cells of the CNS and are implicated in the pathogenesis of various neurodegenerative diseases, including multiple sclerosis (MS) and glaucoma, which affects the visual system. However, the exact roles of microglia in these diseases remain unknown. Herein, we report that DOCK8 is expressed in microglia but not in neurons or astrocytes and that its expression is increased during neuroinflammation. To define the role of DOCK8 in microglial activity, we focused on the retina, a tissue devoid of infiltrating T cells. The retina is divided into distinct layers, and in a disease model of MS/optic neuritis, DOCK8-deficient mice exhibited a clear reduction in microglial migration through these layers. Moreover, neuroinflammation severity, indicated by clinical scores, visual function, and retinal ganglion cell (RGC) death, was reduced in the DOCK8-deficient mice. Furthermore, using a glaucoma disease model, we observed impaired microglial phagocytosis of RGCs in DOCK8-deficient mice. Our data demonstrate that DOCK8 is expressed in microglia and regulates microglial activity in disease states. These findings contribute to a better understanding of the molecular pathways involved in microglial activation and implicate a role of DOCK8 in several neurological diseases.
Source: Journal of Biological Chemistry
Institution: Tokyo Metropolitan Institute of Medical Science
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: The function of Dock3 in neuroprotection and neuroregeneration, New therapy of multiple sclerosis through regulating cell-type specific ASK1 and Dock proteins, Optic nerve regeneration by utilizing neurotrophic factor signaling, Establishment of animal models of neurodegenerative diseases and development of therapeutic strategies utilizing optogenetics, Development of neuroprotective strategies for treatment of neurodegenerative diseases, Generation of a marmoset model of normal tension glaucoma and investigation into neuroprotection and neuroregeneration for glaucoma therapy
OpenAlex ID: W2963552727