Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease

Nat Commun. 2018 May 15;9(1):1899. doi: 10.1038/s41467-018-04269-7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Alexander Disease / genetics
  • Alexander Disease / metabolism*
  • Alexander Disease / psychology
  • Animals
  • Behavior, Animal
  • Biomechanical Phenomena
  • Brain / metabolism
  • Brain Chemistry
  • Child
  • Child, Preschool
  • Drosophila
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippo Signaling Pathway
  • Humans
  • Infant
  • Lamin Type A / genetics
  • Lamin Type A / metabolism
  • Male
  • Mechanotransduction, Cellular*
  • Mice
  • Mice, Transgenic
  • Neuroglia / chemistry
  • Neuroglia / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Young Adult

Substances

  • Glial Fibrillary Acidic Protein
  • Lamin Type A
  • Protein Serine-Threonine Kinases