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 language | English |
|---|---|
| Pages (from-to) | 585-597 |
| Number of pages | 13 |
| Journal | Journal of Neurochemistry |
| Volume | 146 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Sep 1 2018 |
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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 journal › Article
}
TY - JOUR
T1 - Differential toxicity of TAR DNA-binding protein 43 isoforms depends on their submitochondrial localization in neuronal cells
AU - Salvatori, Illari
AU - Ferri, Alberto
AU - Scaricamazza, Silvia
AU - Giovannelli, Ilaria
AU - Serrano, Alessia
AU - Rossi, Simona
AU - D'Ambrosi, Nadia
AU - Cozzolino, Mauro
AU - Giulio, Andrea Di
AU - Moreno, Sandra
AU - Valle, Cristiana
AU - Carrì, Maria Teresa
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.).
AB - 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.).
KW - amyotrophic lateral sclerosis
KW - Complex I
KW - localization
KW - mitochondria
KW - neurodegeneration
KW - TDP-43
UR - http://www.scopus.com/inward/record.url?scp=85053611348&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053611348&partnerID=8YFLogxK
U2 - 10.1111/jnc.14465
DO - 10.1111/jnc.14465
M3 - Article
AN - SCOPUS:85053611348
VL - 146
SP - 585
EP - 597
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 5
ER -