The amyloidogenicity of a C-terminal region of TDP-43 implicated in Amyotrophic Lateral Sclerosis can be affected by anions, acetylation and homodimerization

Biochimie
Archana PrasadBasant K Patel

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 accelerat...Continue Reading

Citations

Mar 1, 2019·The Journal of Biological Chemistry·W Michael BabinchakWitold K Surewicz
Jan 11, 2020·Frontiers in Molecular Neuroscience·Liberty François-MoutalMay Khanna
Mar 7, 2019·Frontiers in Molecular Neuroscience·Archana PrasadBasant K Patel
Nov 13, 2020·Journal of Neurology, Neurosurgery, and Psychiatry·Eva Maria Johanna de BoerSteve Vucic
Mar 2, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Vidhya BharathiBasant K Patel
Apr 10, 2021·The Journal of Physical Chemistry. B·Sydney O Shuster, Jennifer C Lee

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