Different aggregation states of a nuclear localization signal-tagged 25-kDa C-terminal fragment of TAR RNA/DNA-binding protein 43 kDa

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
Akira KitamuraMasataka Kinjo

Abstract

The mechanism and cause of motor neuronal cell death in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder, are unknown; gain of function of oligomers and aggregation of misfolded proteins, including carboxyl-terminal fragments (CTFs) of TAR RNA/DNA-binding protein 43 kDa (TDP-43), have been proposed as important causative factors in the onset of ALS. We recently reported that a nuclear localization signal (NLS)-tagged 25-kDa CTF of TDP-43 (TDP25) could decrease the cell-death proportion compared with that promoted by TDP25. Here, we show oligomeric states of NLS-TDP25 and its detailed localization property using super-resolution fluorescence microscopy, FRET, fluorescence recovery after photobleaching, and fluorescence correlation spectroscopy analysis. NLS-TDP25 efficiently formed a nucleolar cap structure via RNA binding in the presence of actinomycin D, but TDP25 did not. Although cytoplasmic inclusion bodies including TDP25 had a disordered and immobile structure, NLS-TDP25 in the nucleolus was ordered and dynamic. In the diffuse state, TDP25 formed fewer oligomers and interacted with the molecular chaperone, HSP70; however, NLS-TDP25 formed oligomers. These results suggested that NLS-tagged TDP2...Continue Reading

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Citations

Mar 24, 2018·International Journal of Molecular Sciences·Akira Kitamura, Masataka Kinjo
Aug 18, 2020·Molecular Neurodegeneration·Terry R Suk, Maxime W C Rousseaux
Sep 16, 2017·Genes & Development·Erin G Conlon, James L Manley
Mar 7, 2019·Frontiers in Molecular Neuroscience·Archana PrasadBasant K Patel
Jul 3, 2021·International Journal of Molecular Sciences·Han-Jou Chen, Jacqueline C Mitchell

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