Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease

• Main Authors: Wang, Liqun (Author), Xia, Jing (Contributor), Li, Jonathan (Contributor), Hagemann, Tracy L. (Author), Jones, Jeffrey R. (Author), Fraenkel, Ernest (Contributor), Weitz, David A. (Author), Zhang, Su-Chun (Author), Messing, Albee (Author), Feany, Mel B. (Author)
• Other Authors: Massachusetts Institute of Technology. Computational and Systems Biology Program (Contributor), Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory (Contributor), Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2018-09-05T18:06:06Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Institute of Child Health and Human Development (U.S.) (P01HD076892)
National Institute of Child Health and Human Development (U.S.) (U54HD090255)
National Institute of Child Health and Human Development (U.S.) (U54HD090256)
National Science Foundation (U.S.). Division of Materials Research (DMR-1310266)
National Science Foundation (U.S.). Division of Materials Research (DMR-1420570)
National Institutes of Health (U.S.) (P01HL120839-03)
National Institutes of Health (U.S.) (P01GM096971)