Abstract
Astrocytes are abundant glial cells in the central nervous system (CNS) that perform diverse functions in health and disease. Astrocyte dysfunction is found in numerous diseases, including multiple sclerosis, Alzheimer disease, Parkinson disease, Huntington disease and neuropsychiatric disorders. Astrocytes regulate glutamate and ion homeostasis, cholesterol and sphingolipid metabolism and respond to environmental factors, all of which have been implicated in neurological diseases. Astrocytes also exhibit significant heterogeneity, driven by developmental programmes and stimulus-specific cellular responses controlled by CNS location, cell–cell interactions and other mechanisms. In this Review, we highlight general mechanisms of astrocyte regulation and their potential as therapeutic targets, including drugs that alter astrocyte metabolism, and therapies that target transporters and receptors on astrocytes. Emerging ideas, such as engineered probiotics and glia-to-neuron conversion therapies, are also discussed. We further propose a concise nomenclature for astrocyte subsets that we use to highlight the roles of astrocytes and specific subsets in neurological diseases.
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Acknowledgements
Research in the Quintana lab is supported by grants NS102807, ES02530, ES029136, AI126880 and AI149699 from the NIH; RG4111A1 from the National Multiple Sclerosis Society (to F.J.Q.), and PA-1604-08459 from the International Progressive MS Alliance. H.-G.L. was supported by a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1A6A3A14039088). M.A.W. was supported by the NIH (1K99NS114111, F32NS101790), a training grant from the NIH and Dana-Farber Cancer Institute (T32CA207201), a travelling neuroscience fellowship from the Program in Interdisciplinary Neuroscience at Brigham and Women’s Hospital, and the Women’s Brain Initiative at Brigham and Women’s Hospital.
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Glossary
- Tripartite synapses
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Bidirectional interactions established by astrocytes with pre- and post-synaptic nerve terminals.
- Excitotoxicity
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Neuronal dysfunction and death caused by the accumulation of excess neurotransmitters, primarily glutamate, in synapses.
- Relapsing–remitting mutiple sclerosis
-
(RRMS). The most common phenotype of multiple sclerosis, which is characterized by relapses followed by periods of partial or complete recovery. Most patients with RRMS will eventually develop secondary progressive multiple sclerosis.
- Secondary progressive multiple sclerosis
-
(SPMS). A phase of multiple sclerosis characterized by the progressive, irreversible accumulation of neurological disability, which shows limited response to available therapies.
- Gut–brain axis
-
(GBA). Bidirectional communication between the gut microbiota and the brain.
- Astrocyte–neuron lactate shuttle
-
Mechanism by which lactate released by astrocytes from glycolysis is used as a metabolic substrate for neurons under normal physiological conditions.
- Designer receptors exclusively activated by designer drugs
-
(DREADDs). Widely used tool for selectively manipulating neuronal activity indirectly through G protein-coupled receptor (GPCR)-dependent signalling pathways.
- Medium spiny neuron
-
(MSN). Class of inhibitory GABAergic neurons that represents ~95% of the neuronal population in the mammalian striatum.
- Synaptic pruning
-
Neurodevelopmental process of eliminating neurons and synaptic connections in the brain.
- Photoactivatable Ca2+ uncaging
-
Covalent attachment of a photochemical group to a biomolecule to render it inert until light irradiation releases the bond. In the case of Ca2+ uncaging, the photochemical group is attached to a Ca2+ chelator, such as EGTA.
- Poly(lactic-co-glycolic acid) nanoparticles
-
(PLGA nanoparticles). FDA-approved biodegradable polymeric nanoparticle extensively used in drug delivery systems owing to its biocompatibility and low toxicity.
- Polyamidoamine dendrimers
-
(PAMAM dendrimers). A class of dendrimers, hyperbranched macromolecules with numerous functional amine groups on the surface.
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Lee, HG., Wheeler, M.A. & Quintana, F.J. Function and therapeutic value of astrocytes in neurological diseases. Nat Rev Drug Discov 21, 339–358 (2022). https://doi.org/10.1038/s41573-022-00390-x
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DOI: https://doi.org/10.1038/s41573-022-00390-x
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