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Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease

Citation:

Wang, L. ; Xia, J. ; Li, J. ; Hagemann, T. L. ; Jones, J. R. ; Fraenkel, E. ; Weitz, D. A. ; Zhang, S. - C. ; Messing, A. ; Feany, M. B. Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease. Nat. Commun. 2018, 9 1899. Copy at http://www.tinyurl.com/y6a9xubf
wang2018.pdf4.3 MB

Date Published:

May

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.

Publisher's Version

Last updated on 09/07/2018