Neurotoxicity of Reactive Astrocyte-secreted Lipids in Neurodegenerative Disease

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PROJECT SUMMARY Glaucoma is a neurodegenerative disease of aging that features the death of retinal ganglion cell neurons (RGCs) in the retina, often as a result of prolonged increases in intraocular pressure. This cell death leads to a decrease in visual acuity and ultimately blindness. While glial and immune responses have been associated with glaucoma, little understood about their potential causative role in loss of vision. Reactive astrocytes are increasingly shown to appear well before traditional pathological readouts of a wide range of neurodegenerative diseases, including glaucoma. One subset of reactive astrocytes reported by us and others as putatively neurotoxic. These neurotoxic reactive astrocytes are present in regions of neurodegeneration in human postmortem tissue from patients with multiple diseases of aging, as well as in the retina following acute injury to RGC axons and in a chronic retinal degeneration in a bead occlusion model of glaucoma. Preventing formation of neurotoxic reactive astrocytes prevents death of neurons, and spared neurons are electrophysiologically functional and thus still have potential value for regeneration following injury and in disease. We now report that these reactive astrocytes secrete a potent neurotoxic lipid, specifically long-chain free fatty acids, that induce death of neurons, both in vitro and in vivo. Block of the enzyme involved in production of toxic lipids, Elovl1, in astrocytes preserves neuron numbers. Together, these findings highlight a subset of reactive astrocytes as drivers of RGC death in a chronic neurodegenerative disease of the eye. Here we will investigate the role of reactive astrocyte-derived toxic lipids to determine the timing and mechanism of reactive astrocytes in driving death of RGC somas in the retina, during acute and chronic injury to the eye. We will focus on three broad research questions: is the PERK-ATF3 pathway required to drive neuron cell death by astrocyte toxic lipids? Does blocking neurotoxic reactive astrocytes preserve neuronal function and visual acuity in a mouse model of glaucoma? And what is the requirement for neuronal susceptibility prior to astrocyte-induced cell death? We will determine maintenance of optic nerve axons using a mouse model deficient for neurotoxic lipids released by reactive astrocytes in combination with investigating changes in visual acuity in glaucomatous mice using both wildtype and toxic lipid-deficient mice to determine if targeting reactive astrocytes can preserve vision. We will also investigate individual components of the PERK-ATF3 mediated lipoapoptosis pathway – a putative mechanism by which reactive astrocyte secreted toxic lipids drive death of neurons. This proposal will investigate a novel approach to maintain vision during glaucoma. It will provide for the first time a connection between astrocyte reactivity, RGC health, visual acuity, and thalamic synaptic connections.