A link between stress granules and pathological inclusions of TDP-43.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases characterized by the presence of neuropathological aggregates of phosphorylated TDP-43. The TDP-43 protein is also a component of stress granules. Stress granules are cytoplasmic vesicles that form when a cell experiences intense stress conditions. Under these conditions the cell considerably reduces its production of proteins.

So almost all of the studies aiming at reproducing TDP-43 inclusions have been carried out under conditions of intense short-term stress, which differ significantly from the chronic stress conditions occurring in neurodegeneration.

In addition, most of the studies have been done using immortalized cell lines, which are very different from natural cells.

In the article which is the subject of this post and which was posted on the pre-print server BioRxiv, the authors show that a state of mild but prolonged oxidative stress, leads to the formation of stress granules in primary fibroblasts and neurons derived from iPSC in both controls and ALS patients.

In their experiment, primary fibroblasts and neurons derived from induced pluripotent stem cells from ALS patients carrying mutations in the TARDBP (n = 3) and C9ORF72 (n = 3) genes and healthy controls (n = 3) were exposed to oxidative stress by sodium arsenite.

The formation of stress granules and the cellular response to stress were evaluated and quantified by immunofluorescence and electron microscopy analyzes. The scientists found that not only an acute, but also a chronic oxidative insult, is capable of inducing the formation of stress granules in primary fibroblasts and neurons derived from iPSC.

The researchers assume that, when stress is chronic, as in neurodegeneration, cells carrying a TARDBP mutation show less capacity to induce a long-term protective mechanism, unlike C9ORF72 mutant cells.

Above all, the authors of the article observed the recruitment of TDP-43 in stress granules and the formation of phosphorylated aggregates of TDP-43, very similar to the abnormal inclusions observed in the autoptic ALS / FTD brains, this only in case of chronic stress. In addition, in fibroblasts, the cellular response to stress was different in control compared to mutant ALS cells, probably due to their different vulnerability.

A quantitative analysis also revealed differences in terms of the number of cells forming stress granules and the size of stress granules, suggesting a different composition of the vesicles in acute and chronic stress.

In prolonged stress, the stress granules and the formation of phosphorylated TDP-43 aggregates were concomitant with an increase in p62 and deregulation of autophagy in ALS fibroblasts and iPSC-derived neurons. This alteration in autophagy suggests that prolonged stress alters the cellular mechanism of protein degradation and reduces the ability of stress granules to disassemble properly.

The authors of the article assume that in neurodegeneration, there is a critical stress threshold above which the disassembly of stress granules becomes impossible and causes the quality control of system proteins, including chaperones, to be engulfed, and the autophagic and ubiquitin / proteasome systems.

Cells derived from ALS patients, exposed to persistent oxidative stress, represent an appropriate bioassay to study not only the pathology of TDP-43, but also to test potential drugs capable of preventing or breaking down phosphorylated inclusions of TDP-43 .

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