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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Authors | Liqun Wang, Jing Xia, Jonathan Li, Tracy L Hagemann, Jeffrey R Jones, Ernest Fraenkel, David A Weitz, Su-Chun Zhang, Albee Messing, Mel B Feany |
Journal | Nature communications
(Nat Commun)
Vol. 9
Issue 1
Pg. 1899
(05 15 2018)
ISSN: 2041-1723 [Electronic] England |
PMID | 29765022
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Glial Fibrillary Acidic Protein
- Lamin Type A
- Protein Serine-Threonine Kinases
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Topics |
- Adolescent
- Adult
- Alexander Disease
(genetics, metabolism, 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, metabolism)
- Male
- Mechanotransduction, Cellular
- Mice
- Mice, Transgenic
- Neuroglia
(chemistry, metabolism)
- Protein Serine-Threonine Kinases
(genetics, metabolism)
- Young Adult
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