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. (2018). Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease.  Nat. Commun. 9(1): 1899.

FBrf0241275

Research paper

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.

PMC5954157 (PMC) (EuropePMC)