Full-length TDP-43 and its C-terminal domain form filamentsin vitrohaving non-amyloid properties

Year: 2020

Authors: Capitini C., Fani G., Vega MV., Penco A., Canale C., Cabrita LD., Calamai M., Christodoulou J., Relini A., Chiti F.

Autors Affiliation: Univ Florence, Dept Expt & Clin Biomed Sci, Sect Biochem, Florence, Italy; European Lab Nonlinear Spect, Sesto Fiorentino, Italy; Univ Genoa, Dept Phys, Genoa, Italy; UCL, Inst Struct & Mol Biol, London, England; Birkbeck Coll London, London, England; CNR, Natl Inst Opt, Sesto Fiorentino, Italy

Abstract: Accumulation of ubiquitin-positive, tau- and alpha-synuclein-negative intracellular inclusions of TDP-43 in the central nervous system represents the major hallmark correlated to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Such inclusions have variably been described as amorphous aggregates or more structured deposits having amyloid properties. Here we have purified full-length TDP-43 (FL TDP-43) and its C-terminal domain (Ct TDP-43) to investigate the morphological, structural and tinctorial features of aggregates formedin vitroby them at pH 7.4 and 37 degrees C. AFM images indicate that both protein variants show a tendency to form filaments. Moreover, we show that both FL TDP-43 and Ct TDP-43 filaments possess a largely disordered secondary structure, as ascertained by far-UV circular dichroism and Fourier transform infra-red spectroscopy, do not bind Congo red and induce a very weak increase of thioflavin T fluorescence, indicating the absence of a clear amyloid-like signature.


Volume: xxxx      Pages from: ea07 Oct 2  to: ea07 Oct 2

KeyWords: Motor neuron disease; TDP-43 fibrils; TDP-43 filaments; protein misfolding; protein aggregation
DOI: 10.1080/13506129.2020.1826425

Citations: 6
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