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

Publication ,  Journal Article
Tang, AT; Sullivan, KR; Hong, CC; Goddard, LM; Mahadevan, A; Ren, A; Pardo, H; Peiper, A; Griffin, E; Tanes, C; Mattei, LM; Yang, J; Li, L ...
Published in: Sci Transl Med
November 27, 2019

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.

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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

November 27, 2019

Volume

11

Issue

520

Location

United States

Related Subject Headings

  • Toll-Like Receptor 4
  • Signal Transduction
  • Proto-Oncogene Proteins
  • Mice
  • Membrane Proteins
  • Ligands
  • KRIT1 Protein
  • Intestinal Mucosa
  • Humans
  • Hemangioma, Cavernous, Central Nervous System
 

Citation

APA
Chicago
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Tang, A. T., Sullivan, K. R., Hong, C. C., Goddard, L. M., Mahadevan, A., Ren, A., … Kahn, M. L. (2019). Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci Transl Med, 11(520). https://doi.org/10.1126/scitranslmed.aaw3521
Tang, Alan T., Katie R. Sullivan, Courtney C. Hong, Lauren M. Goddard, Aparna Mahadevan, Aileen Ren, Heidy Pardo, et al. “Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.Sci Transl Med 11, no. 520 (November 27, 2019). https://doi.org/10.1126/scitranslmed.aaw3521.
Tang AT, Sullivan KR, Hong CC, Goddard LM, Mahadevan A, Ren A, et al. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci Transl Med. 2019 Nov 27;11(520).
Tang, Alan T., et al. “Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.Sci Transl Med, vol. 11, no. 520, Nov. 2019. Pubmed, doi:10.1126/scitranslmed.aaw3521.
Tang AT, Sullivan KR, Hong CC, Goddard LM, Mahadevan A, Ren A, Pardo H, Peiper A, Griffin E, Tanes C, Mattei LM, Yang J, Li L, Mericko-Ishizuka P, Shen L, Hobson N, Girard R, Lightle R, Moore T, Shenkar R, Polster SP, Rödel CJ, Li N, Zhu Q, Whitehead KJ, Zheng X, Akers A, Morrison L, Kim H, Bittinger K, Lengner CJ, Schwaninger M, Velcich A, Augenlicht L, Abdelilah-Seyfried S, Min W, Marchuk DA, Awad IA, Kahn ML. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci Transl Med. 2019 Nov 27;11(520).

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

November 27, 2019

Volume

11

Issue

520

Location

United States

Related Subject Headings

  • Toll-Like Receptor 4
  • Signal Transduction
  • Proto-Oncogene Proteins
  • Mice
  • Membrane Proteins
  • Ligands
  • KRIT1 Protein
  • Intestinal Mucosa
  • Humans
  • Hemangioma, Cavernous, Central Nervous System