TDP-43 is one of the few proteins capable of becoming altered in ways that allow it to form solid aggregates. Like many of the other examples, it is involved in the onset and progression of neurodegenerative conditions. This form of pathology in the brain was a more recent discovery than, for example, the involvement of amyloid-β and tau in Alzheimer's disease or α-synuclein in Parkinson's disease. It was only a few years ago that researchers clearly defined limbic-predominant age-related TDP-43 encephalopathy (LATE) as a novel form of neurodegenerative condition. Separately, TDP-43 also appears important in amyotrophic lateral sclerosis (ALS). As research into TDP-43 aggregation broadens, it appears likely that it causes neurodegenerative pathology to some degree in a large fraction of the older population.
In today's open access paper, researchers report on one of the ways in which TDP-43 aggregation can cause harm to the brain. Problems start because aggregation depletes TDP-43 in the cell nucleus, where it serves useful functions. This depletion alters cell behavior in pathological ways. When this happens in cells making up the blood-brain barrier, it causes the blood-brain barrier to leak. Normally the blood-brain barrier prevents unwanted cells and molecules from passing from the circulation into the brain. Leakage produces persistent inflammatory reactions to those unwanted cells and molecules in brain tissue, and this chronic inflammation is disruptive to brain function.
Loss of nuclear TDP-43 (TAR DNA-binding protein 43) is a common feature in a wide range of neurodegenerative diseases. These include Alzheimer's disease (AD), limbic-predominant age-related TDP-43 encephalopathy, and amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Across these diseases, a common feature is aggregation of ubiquitinated TDP-43 in the cytosol and nuclear loss of TDP-43 in neurons. The identification of familial FTD mutations in TDP-43 that exacerbate this process highlights TDP-43 dysfunction as a driver in disease progression. Mechanistically, the reduced nuclear levels of TDP-43 are associated with impaired nuclear splicing functions. In a dose-dependent manner, the loss of nuclear TDP-43 results in the aberrant inclusion of exonic junctions into transcripts, often leading to transcript destabilization and degeneration through nonsense-mediated mRNA decay. In neurons, the loss of specific transcripts alters the expression of proteins critical for axonal projection, which is thought to contribute to the progression of motor neuron deficits in ALS.
Early in the course of neurodegenerative diseases, increased flux across the blood-brain barrier (BBB) is detected. BBB leakage alone can exacerbate neurodegenerative changes in animal models. While not all the subsequent consequences of BBB leakage are fully understood, fibrin deposition has been linked to reactive changes in brain microglia. The BBB is part of a complex neurovascular unit comprising endothelial cells (ECs) lining the lumen of vessels, an underlying basement membrane, associated pericytes, astrocytes, and perivascular fibroblasts. Although each of these components contributes to the barrier, it is the ECs that provide the functional barrier.
Here, we show that TDP-43 has a critical function in the maintenance of the BBB. We recently identified reduced nuclear TDP-43 in capillary ECs of donors with ALS-FTD. Because BBB permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD-associated mutation in TDP-43 and that this leads to loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phosphorylated Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43-deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD.
View the full article at FightAging
