Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease

Liqun Wang, Jing Xia, Jonathan Li, Tracy L. Hagemann, Jeffrey R. Jones, Ernest Fraenkel, David A. Weitz, Su-Chun Zhang, Albee Messing and Mel B. Feany ()
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Liqun Wang: Brigham and Women’s Hospital, Harvard Medical School
Jing Xia: Harvard University
Jonathan Li: Massachusetts Institute of Technology
Tracy L. Hagemann: Waisman Center, University of Wisconsin-Madison
Jeffrey R. Jones: Waisman Center, University of Wisconsin-Madison
Ernest Fraenkel: Massachusetts Institute of Technology
David A. Weitz: Harvard University
Su-Chun Zhang: Waisman Center, University of Wisconsin-Madison
Albee Messing: Waisman Center, University of Wisconsin-Madison
Mel B. Feany: Brigham and Women’s Hospital, Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04269-7

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