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A molecular switch for neuroprotective astrocyte reactivity.
- Source :
-
Nature [Nature] 2024 Feb; Vol. 626 (7999), pp. 574-582. Date of Electronic Publication: 2023 Dec 12. - Publication Year :
- 2024
-
Abstract
- The intrinsic mechanisms that regulate neurotoxic versus neuroprotective astrocyte phenotypes and their effects on central nervous system degeneration and repair remain poorly understood. Here we show that injured white matter astrocytes differentiate into two distinct C3-positive and C3-negative reactive populations, previously simplified as neurotoxic (A1) and neuroprotective (A2) <superscript>1,2</superscript> , which can be further subdivided into unique subpopulations defined by proliferation and differential gene expression signatures. We find the balance of neurotoxic versus neuroprotective astrocytes is regulated by discrete pools of compartmented cyclic adenosine monophosphate derived from soluble adenylyl cyclase and show that proliferating neuroprotective astrocytes inhibit microglial activation and downstream neurotoxic astrocyte differentiation to promote retinal ganglion cell survival. Finally, we report a new, therapeutically tractable viral vector to specifically target optic nerve head astrocytes and show that raising nuclear or depleting cytoplasmic cyclic AMP in reactive astrocytes inhibits deleterious microglial or macrophage cell activation and promotes retinal ganglion cell survival after optic nerve injury. Thus, soluble adenylyl cyclase and compartmented, nuclear- and cytoplasmic-localized cyclic adenosine monophosphate in reactive astrocytes act as a molecular switch for neuroprotective astrocyte reactivity that can be targeted to inhibit microglial activation and neurotoxic astrocyte differentiation to therapeutic effect. These data expand on and define new reactive astrocyte subtypes and represent a step towards the development of gliotherapeutics for the treatment of glaucoma and other optic neuropathies.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Adenylyl Cyclases metabolism
Cell Differentiation
Cell Nucleus metabolism
Cell Survival
Cyclic AMP metabolism
Cytoplasm metabolism
Macrophages metabolism
Macrophages pathology
Microglia metabolism
Microglia pathology
Optic Nerve Injuries metabolism
Optic Nerve Injuries pathology
Optic Nerve Injuries therapy
Retinal Ganglion Cells cytology
Retinal Ganglion Cells metabolism
White Matter metabolism
White Matter pathology
Glaucoma pathology
Glaucoma therapy
Astrocytes cytology
Astrocytes enzymology
Astrocytes metabolism
Neuroprotection
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 626
- Issue :
- 7999
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 38086421
- Full Text :
- https://doi.org/10.1038/s41586-023-06935-3