Defects in the blood vessel network of the central nervous system have been linked to early symptoms of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). It is this complex vascular network that provides the necessary nutrients — especially glucose and oxygen — to activate all neuronal functions. Now, a study reveals that the TDP-43 protein is essential for forming a stable and mature blood vessel network in the central nervous system.
According to the study, featured on the cover of the journal JCI Insight, the TDP-43 protein is also critical in maintaining the integrity of the blood-brain barrier, which prevents toxins and pathogens from reaching the central nervous system.
The TDP-43 protein is a key factor in nervous system function and neuronal plasticity. It is a DNA- and RNA-binding protein that regulates gene expression, and its dysfunction has been associated with various neurodegenerative disorders.
Although much progress has been made recently in understanding the functions of TDP-43 in neurons, its exact role in the endothelial cells that make up the circulatory system, the formation of new blood vessels (angiogenesis) and vascular function was not yet known.
"The study reveals for the first time that TDP-43 is essential for the formation and stability of blood vessels in the central nervous system, and for the integrity of the blood-brain barrier", says the senior author .
The vascularization of the central nervous system and the formation of the blood-brain barrier are regulated by different signalling pathways. For example, the integrin signalling pathway that regulates the interaction of cells with the extracellular matrix and the signalling carried out by the transcription factor β-catenin.
"In the study, we found that TDP-43 deficiency alters the extracellular matrix that surrounds blood vessels and reduces β-catenin signalling in endothelial cells", says the researcher. "Thus, mice without endothelial TDP-43 protein show multiple haemorrhages and vascular degeneration in the brain and spinal cord.”
The authors also identify TDP-43 in endothelial cells as a potential contributing factor to the vascular defects that trigger the inflammatory response observed in patients diagnosed with TDP-43-associated diseases.
"Some alterations in the blood vessels of the central nervous system — defects in the integrity of the blood-brain barrier or degeneration of endothelial cells — are associated with inflammatory and immune responses that can cause neuronal loss. This process of neuronal degeneration underlies the origin or progression of various neurological disorders — stroke, diabetic retinopathy — and some neurodegenerative diseases such as Alzheimer's disease, ALS or LATE (Limbic-predominant age-related TDP- 43 encephalopathy).
The study will help to better understand the molecular mechanisms linking vascular defects and neuroinflammation. "Our goal now is to analyse whether defects in TDP-43 protein function in the endothelium of mature vessels could be involved in ALS or other TDP-43-associated pathologies due to increased vascular permeability or inflammatory processes," the author concludes.
https://insight.jci.org/articles/view/177819
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fendothelial-tdp-43&filter=22
Blood-brain barrier protein may be altered in some neurodegenerative diseases
- 545 views
- Added
Edited
Latest News
How the brain fine-tunes it…
By newseditor
Posted 25 Apr
Immune cells carry a long-l…
By newseditor
Posted 25 Apr
Mutations in noncoding DNA…
By newseditor
Posted 24 Apr
More influence of environme…
By newseditor
Posted 24 Apr
The assembly of the human c…
By newseditor
Posted 24 Apr
Other Top Stories
Relapse of intestinal disease by the disturbance in microbial network
Read more
Small metabolites protect against the intestinal infection
Read more
How chronic gum disease may lead to Alzheimer's disease
Read more
Mechanism of action of anti-malaria drug in the brain
Read more
Set of genes predicts severity of dengue
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Systematic characterization…
By newseditor
Posted 27 Apr
The MYCN 50 UTR as a therap…
By newseditor
Posted 25 Apr
Control of neuronal excitat…
By newseditor
Posted 25 Apr
Epithelial UNC-23 limits me…
By newseditor
Posted 25 Apr
Macrophage memories of earl…
By newseditor
Posted 25 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar