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- W2900484493 endingPage "413" @default.
- W2900484493 startingPage "397" @default.
- W2900484493 abstract "We investigated the Central Nervous System (CNS) and skeletal muscle tissue from A woman was clinically diagnosed with amyotrophic lateral sclerosis (ALS) at the age of 22. Neuropathologic evaluation showed upper and lower motor neuron loss, corticospinal tract degeneration and skeletal muscle denervation. Analysis of the patient's Deoxyribonucleic acid (DNA) revealed a AGT>GGT change resulting in an S375G substitution in the C-terminal region of TDP-43. This variant was previously reported as being benign. Considering the early onset and severity of the disease in this patient, we tested the effects of this genetic variant on TDP-43 localization, pre-mRNA splicing activity and toxicity, in parallel with the effects on known neighboring disease-associated mutations. In cell lines, expressed in culture, S375G TDP-43 appeared to be more significantly localized in the nucleus and to exert higher toxicity than wild-type TDP-43. Strikingly, a phosphomimic mutant at the same residue (S375E) showed a strong tendency to accumulate in the cytoplasm, especially under stress conditions, and molecular dynamics simulations suggest that phosphorylation of this residue can disrupt TDP-43 intermolecular interactions. The results of the current study highlight the importance of phosphorylation and regulation of TDP-43 nuclear-cytoplasmic shuttling/redistribution, in relation to the pathogenetic mechanisms involved in different forms of ALS." @default.
- W2900484493 created "2018-11-29" @default.
- W2900484493 creator A5006206320 @default.
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- W2900484493 creator A5032436476 @default.
- W2900484493 creator A5039892218 @default.
- W2900484493 creator A5042658190 @default.
- W2900484493 creator A5047929315 @default.
- W2900484493 creator A5058244935 @default.
- W2900484493 creator A5059112615 @default.
- W2900484493 creator A5064132072 @default.
- W2900484493 creator A5074034334 @default.
- W2900484493 creator A5083854775 @default.
- W2900484493 date "2018-12-27" @default.
- W2900484493 modified "2023-10-18" @default.
- W2900484493 title "Dysregulation of TDP‐43 intracellular localization and early onset ALS are associated with a <i>TARDBP</i> S375G variant" @default.
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