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

Prasad, Archana and Sivalingam, Vishwanath and Bharathi, Vidhya and Girdhar, Amandeep and Patel, Basant Kumar (2018) The amyloidogenicity of a C-terminal region of TDP-43 implicated in Amyotrophic Lateral Sclerosis can be affected by anions, acetylation and homodimerization. Biochimie. ISSN 0300-9084 (In Press)

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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.

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IITH Creators:
IITH CreatorsORCiD
Patel, Basant Kumarhttp://orcid.org/0000-0001-9465-4803
Item Type: Article
Uncontrolled Keywords: TDP-43; ALS; Amyloid; Hofmeister effect; Acetylation; Homodimerization
Subjects: Others > Biotechnology
Divisions: Department of Biotechnology
Depositing User: Team Library
Date Deposited: 15 May 2018 07:59
Last Modified: 15 May 2018 08:05
URI: http://raiithold.iith.ac.in/id/eprint/3921
Publisher URL: http://doi.org/10.1016/j.biochi.2018.05.003
OA policy: http://www.sherpa.ac.uk/romeo/issn/0300-9084/
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