Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease

Nature Communications
Liqun WangMel B Feany

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.

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Citations

May 2, 2020·The European Journal of Neuroscience·Chloe M HallGraham K Sheridan
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Methods Mentioned

BETA
transgenic
rheometry
ChIP-Seq
dot blots
PCR

Software Mentioned

iRefIndex verion
DRSC Integrative Ortholog Prediction Tool ( DIOPT )
GraphPad Prism
Huygens
iRefIndex13

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Alexander Disease

Alexander disease is a rare leukodystrophy caused by mutations in the astrocyte-specific intermediate filament protein glial fibrillary acidic protein (GFAP). Here is the latest research on this disease.

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