Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation

Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1126/scitranslmed.aaw3521
Journal or Publication Title: Science Translational Medicine
Volume: 11
Number: 520
Page Range: eaaw3521
Date: 2019
Divisions: Cell Signalling
Depositing User: General Admin
Identification Number: 10.1126/scitranslmed.aaw3521
ISSN: 1946-6234
Date Deposited: 22 Dec 2020 02:48
Abstract:

Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10 Disease onset is earlier and more severe in individuals with PDCD10 mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with PDCD10 mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of Pdcd10, but not Krit1, in gut epithelial cells. Loss of gut epithelial Pdcd10 results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of Pdcd10 in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Creators:
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Tang, Alan T.
UNSPECIFIED
Sullivan, Katie R.
UNSPECIFIED
Hong, Courtney C.
UNSPECIFIED
Goddard, Lauren M.
UNSPECIFIED
Mahadevan, Aparna
UNSPECIFIED
Ren, Aileen
UNSPECIFIED
Pardo, Heidy
UNSPECIFIED
Peiper, Amy
UNSPECIFIED
Griffin, Erin
UNSPECIFIED
Tanes, Ceylan
UNSPECIFIED
Mattei, Lisa M.
UNSPECIFIED
Yang, Jisheng
UNSPECIFIED
Li, Li
UNSPECIFIED
Mericko-Ishizuka, Patricia
UNSPECIFIED
Shen, Le
UNSPECIFIED
Hobson, Nicholas
UNSPECIFIED
Girard, Romuald
UNSPECIFIED
Lightle, Rhonda
UNSPECIFIED
Moore, Thomas
UNSPECIFIED
Shenkar, Robert
UNSPECIFIED
Polster, Sean P.
UNSPECIFIED
Roedel, Claudia J.
UNSPECIFIED
Li, Ning
UNSPECIFIED
Zhu, Qin
UNSPECIFIED
Whitehead, Kevin J.
UNSPECIFIED
Zheng, Xiangjian
UNSPECIFIED
Akers, Amy
UNSPECIFIED
Morrison, Leslie
UNSPECIFIED
Kim, Helen
UNSPECIFIED
Bittinger, Kyle
UNSPECIFIED
Lengner, Christopher J.
UNSPECIFIED
Schwaninger, Markus
UNSPECIFIED
Velcich, Anna
UNSPECIFIED
Augenlicht, Leonard
UNSPECIFIED
Abdelilah-Seyfried, Salim
UNSPECIFIED
Min, Wang
UNSPECIFIED
Marchuk, Douglas A.
UNSPECIFIED
Awad, Issam A.
UNSPECIFIED
Kahn, Mark L.
UNSPECIFIED
Last Modified: 22 Dec 2020 02:48
URI: https://eprints.centenary.org.au/id/eprint/132

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