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Editors Selection IGR 11-1
Basic Science: Astrocytes: what turns them from friend to foe?
Comment by David Calkins on:
117032 A molecular switch for neuroprotective astrocyte reactivity, Cameron EG; Nahmou M; Toth AB et al., Nature, 2024; 626: 574-582
Astrocyte glial cells play multiple functional roles throughout the central nervous system, including in the retina and optic projection. Named for their beautiful stellate appearance, astrocytes mediate critical metabolic, inflammatory, trophic, and immune interactions between neurons and their axons, vascular elements, and other glial cells, especially resident microglia. Astrocytes oscillate between different states, in a process known as reactivity. This term is not only an oversimplification, but also is associated almost entirely with pro-pathogenic processes. In fact, astrocyte phenotypes included both neurotoxic and neuroprotective states, each governed by distinct molecular signatures. Cameron et al. combined sophisticated analysis of astrocyte gene expression, cell culture assays, transgenic mouse modeling and demonstrates that neurotoxic vs. neuroprotective to make several important and novel discoveries stemming from the cAMP (cyclic adenosine monophosphate) signaling pathway.
Their results shine a powerful spotlight on the innovation and utility of modulating intracellular astrocyte signaling cascades using gene therapy for patient-specific interventions tailored to key points in progression
Compartments of cAMP derived from soluble adenylyl cyclase (sAC) influence the balance between toxic vs. protective astrocyte states defined by distinct gene signatures and proliferation, which inhibits microglial activation and further astrocyte toxicity. Using a novel gene therapeutic that targets specifically optic nerve head astrocytes, the team showed that depleting cytoplasmic and increasing nuclear cAMP in astrocytes promotes retinal ganglion cell survival with nerve injury by inhibiting local microglial activity. Thus, sAC and compartmentalized cAMP define a molecular switch for inducing a protective astrocyte phenotype. Tweaking astrocyte molecular responses in glaucoma could be a critical step forward for treating optic nerve degeneration in the disease, especially for patients who progress despite efforts to manage intraocular pressure. For example, astrocyte metabolic support of ganglion cell axons in the retina and optic nerve is important for slowing progression early in animal models of glaucoma. The approach taken in the study by Cameron et al. could be modified to influence astrocyte bioenergetics. Their results shine a powerful spotlight on the innovation and utility of modulating intracellular astrocyte signaling cascades using gene therapy for patient-specific interventions tailored to key points in progression.
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