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

Illari Salvatori, Alberto Ferri, Silvia Scaricamazza, Ilaria Giovannelli, Alessia Serrano, Simona Rossi, Nadia D'Ambrosi, Mauro Cozzolino, Andrea Di Giulio, Sandra Moreno, Cristiana Valle, Maria Teresa Carrì

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 cause of mitochondrial damage. This in turn may cause oxidative stress inducing toxic oligomers formation, in which short TDP-43 forms play a major role. (Figure presented.).

Original languageEnglish
Pages (from-to)585-597
Number of pages13
JournalJournal of Neurochemistry
Volume146
Issue number5
DOIs
Publication statusPublished - Sep 1 2018

Fingerprint

DNA-Binding Proteins
Toxicity
Protein Isoforms
Poisons
Amyotrophic Lateral Sclerosis
Neurodegenerative diseases
Mitochondria
Oxidative stress
RNA-Binding Proteins
Oligomers
Metabolism
Neurodegenerative Diseases
Cytoplasm
Oxidative Stress
Messenger RNA
Proteins

Keywords

  • amyotrophic lateral sclerosis
  • Complex I
  • localization
  • mitochondria
  • neurodegeneration
  • TDP-43

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Differential toxicity of TAR DNA-binding protein 43 isoforms depends on their submitochondrial localization in neuronal cells. / Salvatori, Illari; Ferri, Alberto; Scaricamazza, Silvia; Giovannelli, Ilaria; Serrano, Alessia; Rossi, Simona; D'Ambrosi, Nadia; Cozzolino, Mauro; Giulio, Andrea Di; Moreno, Sandra; Valle, Cristiana; Carrì, Maria Teresa.

In: Journal of Neurochemistry, Vol. 146, No. 5, 01.09.2018, p. 585-597.

Research output: Contribution to journalArticle

Salvatori, I, Ferri, A, Scaricamazza, S, Giovannelli, I, Serrano, A, Rossi, S, D'Ambrosi, N, Cozzolino, M, Giulio, AD, Moreno, S, Valle, C & Carrì, MT 2018, 'Differential toxicity of TAR DNA-binding protein 43 isoforms depends on their submitochondrial localization in neuronal cells', Journal of Neurochemistry, vol. 146, no. 5, pp. 585-597. https://doi.org/10.1111/jnc.14465
Salvatori, Illari ; Ferri, Alberto ; Scaricamazza, Silvia ; Giovannelli, Ilaria ; Serrano, Alessia ; Rossi, Simona ; D'Ambrosi, Nadia ; Cozzolino, Mauro ; Giulio, Andrea Di ; Moreno, Sandra ; Valle, Cristiana ; Carrì, Maria Teresa. / Differential toxicity of TAR DNA-binding protein 43 isoforms depends on their submitochondrial localization in neuronal cells. In: Journal of Neurochemistry. 2018 ; Vol. 146, No. 5. pp. 585-597.
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