Title: Astrocytes in Alexander disease exhibit a senescent phenotype
Legend: (A) Bright field images show senescence associated (SA) β-gal staining (blue) in astrocytes (arrows) from a one-year-old patient with Alexander disease (AxD) and not in age-matched control tissue (arrow heads). Tissues were labeled for GFAP (brown) to identify astrocytes. Quantification is shown in the right panel (***p<0.0001, c2 test). (B) Immunofluorescence labeling shows activation of the cyclin-dependent kinase inhibitor p21cip/waf1 in a one-year-old patient with AxD, but not in age matched control tissue (left panels, GFAP labels astrocytes, DAPI labels nuclei). Protein analysis demonstrates increased p21cip/waf1 in brain tissue from AxD patients compared to age-matched controls (right panel, ***p = 0.0001, unpaired t-test).
Citation: Wang, L., Bukhari, H., Kong, L., Hagemann, T. L., Zhang, S. C., Messing, A., & Feany, M. B. (2022). Anastasis Drives Senescence and Non-Cell Autonomous Neurodegeneration in the Astrogliopathy Alexander Disease. The Journal of neuroscience : the official journal of the Society for Neuroscience, 42(12), 2584–2597. https://doi.org/10.1523/JNEUROSCI.1659-21.2021
Abstract: Anastasis is a recently described process in which cells recover after late-stage apoptosis activation. The functional consequences of anastasis for cells and tissues are not clearly understood. Using Drosophila, rat and human cells and tissues, including analyses of both males and females, we present evidence that glia undergoing anastasis in the primary astrogliopathy Alexander disease subsequently express hallmarks of senescence. These senescent glia promote non-cell autonomous death of neurons by secreting interleukin family cytokines. Our findings demonstrate that anastasis can be dysfunctional in neurologic disease by inducing a toxic senescent population of astroglia. SIGNIFICANCE STATEMENT: Under some conditions cells otherwise destined to die can be rescued just before death in a process called anastasis, or “rising from the dead.” The fate and function of cells undergoing a near death experience is not well understood. Here, we find that in models and patient cells from Alexander disease, an important brain disorder in which glial cells promote neuronal dysfunction and death, anastasis of astrocytic glia leads to secretion of toxic signaling molecules and neurodegeneration. These studies demonstrate a previously unexpected deleterious consequence of rescuing cells on the brink of death and suggest therapeutic strategies for Alexander disease and related disorders of glia.
About the Lab: The Alexander Disease lab is focused on understanding developmental and pathological aspects of glial cell biology in the nervous system of the mouse, with a particular focus on astrocytes and their major intermediate filament protein, GFAP. Main strategies involve genetic manipulation of glial gene expression using transgenic techniques, and gene targeting in embryonic stem cells to generate mutant strains of mice. Current projects address a variety of topics, such as regulation of gene expression, and the role of GFAP mutations and accumulation in the pathogenesis of AxD. A major effort is devoted to devising novel therapeutic strategies for treatment of this disorder, and identifying biomarkers to permit monitoring severity or progression of the disease.
Investigator: Tracy L. Hagemann, PhD