Differential toxicity of TAR DNA-binding protein 43 isoforms depends on their submitochondrial localization in neuronal cells

Journal of Neurochemistry
Illari SalvatoriMaria Teresa Carrì

Abstract

TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein and a major component of protein aggregates found in amyotrophic lateral sclerosis and several other neurodegenerative diseases. TDP-43 exists as a full-length protein and as two shorter forms of 25 and 35 kDa. Full-length mutant TDP-43s found in amyotrophic lateral sclerosis patients re-localize from the nucleus to the cytoplasm and in part to mitochondria, where they exert a toxic role associated with neurodegeneration. However, induction of mitochondrial damage by TDP-43 fragments is yet to be clarified. In this work, we show that the mitochondrial 35 kDa truncated form of TDP-43 is restricted to the intermembrane space, while the full-length forms also localize in the mitochondrial matrix in cultured neuronal NSC-34 cells. Interestingly, the full-length forms clearly affect mitochondrial metabolism and morphology, possibly via their ability to inhibit the expression of Complex I subunits encoded by the mitochondrial-transcribed mRNAs, while the 35 kDa form does not. In the light of the known differential contribution of the full-length and short isoforms to generate toxic aggregates, we propose that the presence of full-length TDP-43s in the matrix is a primary c...Continue Reading

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Citations

Jul 14, 2020·Frontiers in Cellular Neuroscience·Xu YanXinwen Zhang
Aug 18, 2020·Molecular Neurodegeneration·Terry R Suk, Maxime W C Rousseaux
Feb 12, 2019·Laboratory Investigation; a Journal of Technical Methods and Pathology·Mikayla L HuntleyXinglong Wang
Apr 26, 2019·Journal of Cachexia, Sarcopenia and Muscle·Savina ApolloniCinzia Volonté
Dec 5, 2018·Molecular Neurodegeneration·Ali JawaidPaul E Schulz
Mar 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Elaine PirieStuart A Lipton
Mar 13, 2021·Cellular and Molecular Life Sciences : CMLS·Kazuhide AsakawaKoichi Kawakami
May 1, 2021·Biomedicines·Chantal B Lucini, Ralf J Braun
Aug 25, 2019·Molecular and Cellular Neurosciences·Ju GaoXinglong Wang
Nov 17, 2021·British Journal of Pharmacology·Silvia ScaricamazzaAlberto Ferri

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