7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2-3-dihydro-1h-indol-5-yl)-7h-pyrrolo(2-3-d)pyrimidin-4-amine and Protein-Aggregation--Pathological

7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2-3-dihydro-1h-indol-5-yl)-7h-pyrrolo(2-3-d)pyrimidin-4-amine has been researched along with Protein-Aggregation--Pathological* in 1 studies

Other Studies

1 other study(ies) available for 7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2-3-dihydro-1h-indol-5-yl)-7h-pyrrolo(2-3-d)pyrimidin-4-amine and Protein-Aggregation--Pathological

ArticleYear
Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules.
    The Journal of biological chemistry, 2020, 01-17, Volume: 295, Issue:3

    Insoluble, hyperubiquitylated TAR DNA-binding protein of 43 kDa (TDP-43) in the central nervous system characterizes frontotemporal dementia and ALS in many individuals with these neurodegenerative diseases. The causes for neuropathological TDP-43 aggregation are unknown, but it has been suggested that stress granule (SG) formation is important in this process. Indeed, in human embryonic kidney HEK293E cells, various SG-forming conditions induced very strong TDP-43 ubiquitylation, insolubility, and reduced splicing activity. Osmotic stress-induced SG formation and TDP-43 ubiquitylation occurred rapidly and coincided with colocalization of TDP-43 and SG markers. Washout experiments confirmed the rapid dissolution of SGs, accompanied by normalization of TDP-43 ubiquitylation and solubility. Surprisingly, interference with the SG process using a protein kinase R-like endoplasmic reticulum kinase inhibitor (GSK2606414) or the translation blocker emetine did not prevent TDP-43 ubiquitylation and insolubility. Thus, parallel pathways may lead to pathological TDP-43 modifications independent of SG formation. Using a panel of kinase inhibitors targeting signaling pathways of the osmotic shock inducer sorbitol, we could largely rule out the stress-activated and extracellular signal-regulated protein kinase modules and glycogen synthase kinase 3β. For arsenite, but not for sorbitol, quenching oxidative stress with

    Topics: Acetylcysteine; Adenine; Amyotrophic Lateral Sclerosis; DNA-Binding Proteins; Frontotemporal Dementia; Glycogen Synthase Kinase 3 beta; Heat-Shock Proteins; HEK293 Cells; Humans; Indoles; Mutation; Osmotic Pressure; Oxidative Stress; Protein Aggregation, Pathological; Protein Transport; Signal Transduction; Solubility; Sorbitol; Ubiquitination

2020