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TDP-43 is one of a small number of proteins that can become altered in ways that lead to the formation of solid aggregates that, directly and indirectly, cause cell dysfunction and death in the brain. In the case of TDP-43, this proteopathy contributes to amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and what is now called limbic predominant age-related TDP-43 encephalopathy (LATE). This was a more recent discovery than other aggregates involved in neurodegenerative conditions, such as amyloid-β, tau, and α-synuclein, and so the pace of discovery for TDP-43 is a little faster; more remains to be uncovered of the biochemistry of TDP-43 pathology than is the cost for the other problematic proteins.
In today’s research materials, the scientists involved report on a potential role for TDP-43 in dysfunction of the vasculature and blood-brain barrier in the aging brain. Unmodified TDP-43 appears necessary for a number of processes, and depletion may be a contributing cause of some of the vascular issues seen in neurodegenerative conditions associated with TDP-43 aggregation. An important vascular issue is leakage of the blood-brain barrier, allowing unwanted cells and molecules to enter the brain to cause inflammatory reactions or other damage. That said, the usual challenges apply to the finds here, in that knowing that a mechanism exists doesn’t tell us how important it is versus other mechanisms known to contribute to this problem.
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 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. 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).”
TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein that regulates gene expression, and its malfunction in neurons has been causally associated with multiple neurodegenerative disorders. Although progress has been made in understanding the functions of TDP-43 in neurons, little is known about its roles in endothelial cells (ECs), angiogenesis, and vascular function. Using inducible EC-specific TDP-43-knockout mice, we showed that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity, and blood vessel stability.
Postnatal EC-specific deletion of TDP-43 led to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupted the blood-brain barrier and triggered vascular degeneration. These vascular defects were associated with an inflammatory response in the CNS with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupted the fibronectin matrix around sprouting vessels and reduced β-catenin signaling in ECs. Together, our results indicate that TDP-43 is essential for the formation of a stable and mature vasculature.
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