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• W2800498082 endingPage "87" @default.
• W2800498082 startingPage "76" @default.
• W2800498082 abstract "Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease associated with accumulation of hyper-phosphorylated, and ubiquitinated TAR DNA-binding protein-43 (TDP-43) as inclusion deposits in neuronal cells. Recently, amyloid-like fibrillar aggregates of TDP-43 have been reported from several ALS patients. The C-terminal region of TDP-43 is central to TDP-43's pathological aggregation and most of the familial ALS mutations in the encoding TARDBP gene are located in this domain. Also, aberrant proteolytic cleavages of TDP-43 produce cytotoxic C-terminal fragments of ∼15–35 kDa. The C-terminal end harbours a glycine-rich region and a Q/N rich prion-like aggregation-prone domain which has been shown to form amyloid-like fibrillar aggregates in vitro. Previously, TDP-43 protein has also been shown to undergo several other post-translational modifications such as acetylation and dimerization, however, their effects on TDP-43's amyloid-like in vitro aggregation have not been examined. Towards this, we have here examined effects of anions, acetylation and homodimerization on the in vitro aggregation of a C-terminal fragment (amino acid: 193–414) of TDP-43 termed TDP-432C. We find that kosmotropic anions greatly accelerate whereas chaotropic anions impede its aggregation. Also, we show that acetylation of certain lysines in C-terminal fragments significantly reduces the TDP-432C's amyloid-like aggregation. Furthermore, we separated spontaneously formed cysteine-linked homodimers of the recombinantly purified TDP-432C using size-exclusion chromatography and found that these dimers retain amyloidogenicity. These findings would be of significance to the TDP-43 aggregation-induced pathology in ALS." @default.
• W2800498082 created "2018-05-17" @default.
• W2800498082 creator A5007642934 @default.
• W2800498082 creator A5009897879 @default.
• W2800498082 creator A5030569762 @default.
• W2800498082 creator A5030902878 @default.
• W2800498082 creator A5066041934 @default.
• W2800498082 date "2018-07-01" @default.
• W2800498082 modified "2023-10-05" @default.
• W2800498082 title "The amyloidogenicity of a C-terminal region of TDP-43 implicated in Amyotrophic Lateral Sclerosis can be affected by anions, acetylation and homodimerization" @default.
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