摘要：SummaryAmyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease characterized by the formation of cytoplasmic ubiquitinated TDP-43 protein aggregates in motor neurons. Stress granules (SGs) are stress-induced cytoplasmic protein aggregates containing various neuropathogenic proteins, including TDP-43. Several studies have suggested that SGs are the initial site of the formation of pathogenic ubiquitinated TDP-43 aggregates in ALS neurons. Mutations in theoptineurin(OPTN) andTIA1genes are causative factors of familial ALS with TDP-43 aggregation pathology. We found that both OPTN depletion and ALS-associated OPTN mutations upregulated the TIA1 level in cells recovered from heat shock, and this upregulated TIA1 increased the amount of ubiquitinated TDP-43. Ubiquitinated TDP-43 induced by OPTN depletion was localized in SGs. Our study suggests that ALS-associated loss-of-function mutants of OPTN increase the amount of ubiquitinated TDP-43 in neurons by increasing the expression of TIA1, thereby promoting the aggregation of ubiquitinated TDP-43.Graphical abstractDisplay OmittedHighlights•ALS-linked mutations of optineurin (OPTN) delay clearance of stress granules (SGs).•Depletion of OPTN increases ubiquitinated TDP-43 levels by increasing TIA1•ALS-linked OPTN mutants increase ubiquitinated TDP-43 levels by increasing TIA1•High TIA1 induces aberrant SGs with ubiquitinated TDP-43 and delays SG clearanceBiological sciences; Molecular neuroscience; Cellular neuroscience
