Conclusions of the SIGNAL study in Huntington and implications for treatment of other slowly progressive neurodegenerative diseases

Abstract

Astrogliosis is associated with slowly progressive neurodegenerative/neuroinflammatory diseases, including Huntington’s (HD) and Alzheimer’s (AD). In their normal homeostatic state, astrocytes extend numerous specialised cytoplasmic projections that fully cover brain capillaries and facilitate glucose uptake while also extending projections to synapses that recycle 80% of released excitatory transmitters.1 However, under conditions of diseaserelated stress, they undergo a dramatic transformation in which their actin cytoskeleton collapses, they retract cytoplasmic projections, build up secretory machinery, and switch to synthesis and secretion of soluble biological effectors some ofwhichhave neurotoxic activity and others recruit and activate other inflammatory cells.2 In two recent publications,3.4 we investigated the signals that trigger the striking morphological transformation of astrocytes. Based on the previouswork of our own and others, wewere aware of the important role of the semaphorin 4D:plexin-B1/B2 pathway in triggering collapse of the actin cytoskeleton. Binding of Semaphorin 4D (SEMA4D) ligand to the extracellular domain of plexin-B receptors triggers activation of their cytoplasmic Rho-GTPase activating domain. This leads to the inactivation of Rho kinase which is normally required to initiate a chain of events that prevents cofilin-driven depolymerisation of actin filaments.5 We, therefore, investigated expression of SEMA4D and