Here is an article hypothesizing that the redistribution and aggregation of TDP-43 is caused by repeated cycles of oxidative and osmotic stress followed by a period of recovery.
This is consistent with epidemiological and theoretical modeling studies that multiple events contribute to the pathophysiology of ALS and FTD in a multistep process. However, osmotic stress has hardly ever been associated with ALS or FTD.
The biological pathways involved in the formation of cytoplasmic stress granules are not well understood. In general, cells exposed to osmotic stress shrink due to the efflux of water. This negatively affects the cell in several ways, such as decreased degradation and translation of proteins, impaired enzymatic function.
This had already been explored in an article published in January 2020 which showed that the ubiquitylation and insolubility of pathological changes typical of TDP-43 can be induced by various stress conditions and were independent of stress granule formation.
Cytoplasmic stress granules represent an adaptation system to harsh environmental conditions. This cellular adaptation system is particularly important for neurons which do not regenerate and use neurotransmission systems which continuously generate neurotoxic reactive oxygen species.
However, the mechanism by which nuclear TDP-43 moves through the cytoplasm and is recruited into cytoplasmic stress granules has not yet been elucidated.
In this recent publication, authors who work at universities and institutes in England, Slovenia and New Zealand, show that cycles of osmotic shock and oxidative cell stress are needed to create TDP-43 stress granules.
The TDP-43 protein is recruited into cytoplasmic stress granules when cells undergo oxidative cellular stress.
Scientists worked in vitro on SH-SY5Y cells. It is a cell line of human origin used in scientific research. SH-SY5Y cells are often used as in vitro models of neuronal function and differentiation.
We rarely cite in-vitro studies, as the translation of these results into clinical terms is often improbable. On the other hand, in-vitro studies are interesting for studying certain fundamental cellular mechanisms.
Experiments by Youn-Bok Lee, Christopher E Shaw and colleagues indicate that osmotic cellular stress alone appears to effectively remove TDP-43 from the nucleus, but not form stress granules while oxidative cellular stress produces stress granules for it. cell lacking TDP-43.
So the presence of one of these two cellular stressors did not seem to systematically imply the recruitment of TDP-43 to the cytoplasmic stress granules.
The scientists then applied the osmotic and oxidative cell stress individually, sequentially and also in reverse order. Only the sequential exposure of cells to oxidative and then osmotic cellular stress resulted in an abundance of TDP-43 in the cytoplasm.
At the same time, it was found that the cytoplasmic translocation of TDP-43 was parallel to the translation blockade caused by the phosphorylation of eIF2a. Indeed, the phosphorylation of eIF2a, blocks the translation of proteins, which is one of the mechanisms of protection against the cellular stress.
Recovery from oxidative stress followed by osmotic stress produced small TDP-43 positive foci which were surrounded by TIA-1 positive cytoplasmic stress granules.
Thus, sequential and cyclic stress paradigms may provide a better model for exploring the mechanistic aspects of the pathophysiology of ALS and FTD.
A related article very recently presented the idea that mutations in TDP-43 are much more likely, than the healthy version of TDP-43, to condense into stress granules following repeated cycles of osmotic and oxidative cell stress.
