期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-04269-7
关键词
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资金
- Bloomington Drosophila Stock Center (NIH) [P40OD018537]
- Transgenic RNAi Project (TRiP) at the Harvard Medical School (NIH-NIGMS) [R01GM084947]
- NIH-NICHD [P01HD076892]
- Intellectual and Developmental Disabilities Research Centers at Boston Children's Hospital [U54HD090255]
- Waisman Center [U54HD090256]
- National Science Foundation [DMR-1310266]
- Harvard Materials Research Science and Engineering Center [DMR-1420570]
- NIH [P01HL120839-03, P01GM096971]
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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