A molecular switch for neuroprotective astrocyte reactivity

Evan G. Cameron (), Michael Nahmou, Anna B. Toth, Lyong Heo, Bogdan Tanasa, Roopa Dalal, Wenjun Yan, Pratima Nallagatla, Xin Xia, Sarah Hay, Cara Knasel, Travis L. Stiles, Christopher Douglas, Melissa Atkins, Catalina Sun, Masoumeh Ashouri, Minjuan Bian, Kun-Che Chang, Kristina Russano, Sahil Shah, Mollie B. Woodworth, Joana Galvao, Ramesh V. Nair, Michael S. Kapiloff and Jeffrey L. Goldberg ()
Additional contact information
Evan G. Cameron: Stanford University School of Medicine
Michael Nahmou: Stanford University School of Medicine
Anna B. Toth: Stanford University School of Medicine
Lyong Heo: Stanford University
Bogdan Tanasa: Stanford University School of Medicine
Roopa Dalal: Stanford University School of Medicine
Wenjun Yan: Stanford University School of Medicine
Pratima Nallagatla: Stanford University
Xin Xia: Stanford University School of Medicine
Sarah Hay: Stanford University School of Medicine
Cara Knasel: Stanford University School of Medicine
Travis L. Stiles: University of California, San Diego
Christopher Douglas: University of California, San Diego
Melissa Atkins: Stanford University School of Medicine
Catalina Sun: Stanford University School of Medicine
Masoumeh Ashouri: Stanford University School of Medicine
Minjuan Bian: Stanford University School of Medicine
Kun-Che Chang: Stanford University School of Medicine
Kristina Russano: Stanford University School of Medicine
Sahil Shah: Stanford University School of Medicine
Mollie B. Woodworth: Stanford University School of Medicine
Joana Galvao: Stanford University School of Medicine
Ramesh V. Nair: Stanford University
Michael S. Kapiloff: Stanford University School of Medicine
Jeffrey L. Goldberg: Stanford University School of Medicine

Nature, 2024, vol. 626, issue 7999, 574-582

Abstract: 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)1,2, 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06935-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:626:y:2024:i:7999:d:10.1038_s41586-023-06935-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06935-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().