Wang, LiqunXia, JingLi, JonathanHagemann, Tracy L.Jones, Jeffrey R.Fraenkel, ErnestWeitz, DavidZhang, Su-ChunMessing, AlbeeFeany, Mel2018-06-272018Wang, 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. 2018. “Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease.” Nature Communications 9 (1): 1899. doi:10.1038/s41467-018-04269-7. http://dx.doi.org/10.1038/s41467-018-04269-7.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160363Glial 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.en-USJournal Article2018-06-2710.1038/s41467-018-04269-7