Skip to Main content Skip to Navigation
Journal articles

Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits.

Abstract : Introduction:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL) represents the most common hereditary form of cerebral small vessel disease characterized by early-onsetstroke and premature dementia. It is caused by mutations in the transmembrane receptor Notch3, which promote theaggregation and accumulation of the Notch3 extracellular domain (Notch3-ECD) within blood vessel walls. This processis believed to mediate the abnormal recruitment and dysregulation of additional factors including extracellular matrix(ECM) proteins resulting in brain vessel dysfunction. Based on recent evidence indicating a role for the transforminggrowth factor-β(TGF-β) pathway in sporadic and familial small vessel disease we studied fibronectin, fibrillin-1 andlatent TGF-βbinding protein 1 (LTBP-1), three ECM constituents involved in the regulation of TGF-βbioavailability, inpost-mortembrain tissue from CADASIL patients and control subjects.Results:Fibronectin and fibrillin-1 were found to be enriched in CADASIL vessels without co-localizing with Notch3-ECDdeposits, likely as a result of fibrotic processes secondary to aggregate formation. In contrast, LTBP-1 showed both anaccumulation and a striking co-localization with Notch3-ECD deposits suggesting specific recruitment into aggregates.We also detected increased levels of the TGF-βprodomain (also known as latency-associated peptide, LAP) indicatingdysregulation of the TGF-βpathway in CADASIL development.In vitroanalyses revealed a direct interaction betweenLTBP-1 and Notch3-ECD and demonstrated a specific co-aggregation of LTBP-1 with mutant Notch3.Conclusion:We propose LTBP-1 as a novel component of Notch3-ECD deposits and suggest its involvement inpathological processes triggered by Notch3-ECD aggregation.
Document type :
Journal articles
Complete list of metadatas

Cited literature [45 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-01096342
Contributor : Nadia Taibi <>
Submitted on : Wednesday, December 17, 2014 - 11:58:57 AM
Last modification on : Friday, March 27, 2020 - 3:44:02 AM

File

s40478-014-0096-8.pdf
Publisher files allowed on an open archive

Identifiers

  • HAL Id : inserm-01096342, version 1
  • PUBMED : 25190493

Collections

Citation

Jessica Kast, Patrizia Hanecker, Nathalie Beaufort, Armin Giese, Anne Joutel, et al.. Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits.. Acta Neuropathologica Communications, BioMed Central part of Springer Science, 2014, pp.96. ⟨inserm-01096342⟩

Share

Metrics

Record views

317

Files downloads

369