Albee Messing, VMD, PhD – Slide of the Week

Messing Slide of the Week 2019

Title: Changes in nuclear lamins and mechanical stiffness of the brain caused by GFAP mutations in Alexander disease.

Legend: (A) Double label immunofluorescence staining for A-type lamin (arrows, red) around the nuclear rim of astrocytes in a mouse model of Alexander disease, compared to an age-matched control. GFAP staining (green) labels astrocyte cytoplasm, and DAPI (blue) labels nuclei of all cells. Scale bar = 5 microns. (B) Quantitation of lamin A protein in western blots of white matter from Alexander disease patients compared to age-matched controls. (C) Mechanical stiffness of mouse brain measured by rotational rheometry.

Citation: Wang, L., Xia, J., Li, J., Hagemann, T.L., Jones, J.R., Fraenkel, E., Weitz, D.A., Zhang, S.C., Messing, A., and Feany, M.B. (2018). Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease. Nature Communications 9, 1899.

Abstract: Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial function and secondary non-cell autonomous neuronal injury remain incompletely defined. Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. Further, we take cell biological and biophysical approaches to suggest that brain tissue stiffness is increased in Alexander disease. Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis.

About the Lab: Albee Messing’s 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.

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