Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease
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s41467-018-04269-7.pdf
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4.3 MB
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Author(s)
Wang, Liqun
Xia, Jing
Li, Jonathan
Hagemann, Tracy L.
Jones, Jeffrey R.
Fraenkel, Ernest
Weitz, David A.
Zhang, Su-Chun
Messing, Albee
Feany, Mel B.
Date Issued
May 2018
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Wang, Liqun, Jing Xia, Jonathan Li, Tracy L. Hagemann, Jeffrey R. Jones, Ernest Fraenkel, David A. Weitz, Su-Chun Zhang, Albee Messing, and Mel B. Feany. “Tissue and Cellular Rigidity and Mechanosensitive Signaling Activation in Alexander Disease.” Nature Communications 9, no. 1 (May 15, 2018).
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Computational and Systems Biology Program
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.1038/s41467-018-04269-7
