Abnormal phosphorylation of Ser409/410 of TDP‐43 in FTLD‐U and ALS

Inukai, Yuki; Nonaka, Takashi; Arai, Tetsuaki; Yoshida, Mari; Hashizume, Yoshio; Beach, Thomas G.; Buratti, Emanuele; Baralle, Francisco E.; Akiyama, Haruhiko; Hisanaga, Shin‐ichi; Hasegawa, Masato

doi:10.1016/j.febslet.2008.07.027

Cited by 176 publications

(168 citation statements)

References 22 publications

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“…This supports that TDP-43 is preferentially phosphorylated on the C terminus on at least two different residues (Fig. 1C), consistent with current identification of two phosphorylation sites near the C terminus of TDP-43 in diseased tissues (41,42).…”

Section: Expression Localization and Biochemical Properties Of Recosupporting

confidence: 73%

Multiplex SILAC Analysis of a Cellular TDP-43 Proteinopathy Model Reveals Protein Inclusions Associated with SUMOylation and Diverse Polyubiquitin Chains

Seyfried

Gozal

Dammer

et al. 2010

Molecular & Cellular Proteomics

102

114

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Section: Expression Localization and Biochemical Properties Of Recosupporting

confidence: 73%

Multiplex SILAC Analysis of a Cellular TDP-43 Proteinopathy Model Reveals Protein Inclusions Associated with SUMOylation and Diverse Polyubiquitin Chains

Seyfried

Gozal

Dammer

et al. 2010

Molecular & Cellular Proteomics

102

114

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“…Sporadic and familial forms of FTLD-U and ALS are characterized by cytoplasmic accumulation of insoluble, hyperphosphorylated, ubiquitinated, and proteolytically cleaved C-terminal fragments in affected brain and spinal cord regions. The cytoplasmic accumulation of TDP-43 is associated with a depletion of nuclear [15][16][17][18][19][20][21]. These data suggest that some of these TDP-43 proteinopathies may share common mechanisms of pathogenesis.…”

mentioning

confidence: 82%

Rapamycin Rescues TDP-43 Mislocalization and the Associated Low Molecular Mass Neurofilament Instability

Caccamo

Majumder

Deng

et al. 2009

Journal of Biological Chemistry

143

101

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TDP-43 is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. An ϳ25-kDa C-terminal fragment of TDP-43 accumulates in affected brain regions, suggesting that it may be involved in the disease pathogenesis. Here, we show that overexpression of the 25-kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous fulllength TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular mass neurofilament mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43, whereas inhibition of mTOR, a key protein kinase involved in autophagy regulation, reduces the 25-kDa C-terminal fragment accumulation and restores TDP-43 localization. Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies.TDP-43 (transactive response DNA-binding protein 43) is a conserved and ubiquitously expressed nuclear protein with a theoretical molecular mass of ϳ44 kDa. It is encoded by the TARDBP gene on chromosome 1, which is made of six exons that can be alternatively spliced to yield 11 different isoforms, with the mRNA encoding TDP-43 being the major species (1). Functionally, TDP-43 appears to be involved in exon skipping and alternative splicing (2, 3), and it has also been shown to link different types of nuclear bodies (4). Structural studies have confirmed the presence of two RNA recognition motifs (RRM1 and RRM2) and a glycine-rich C-terminal tail, which is thought to mediate protein-protein interaction (5).Recently, TDP-43 has been shown to be the major pathological protein in a wide range of disorders referred to as TDP-43 proteinopathies (6 -8). These include frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), 2 motor neuron disease, and amyotrophic lateral sclerosis (ALS). These last two disorders have been directly linked to mutations in TDP-43 (9, 10). In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases (11)(12)(13)(14). Sporadic and familial forms of FTLD-U and ALS are characterized by cytoplasmic accumulation of insoluble, hyperphosphorylated, ubiquitinated, and proteolytically cleaved C-terminal fragments in affected brain and spinal cord regions. The cytoplasmic accumulation of TDP-43 is associated with a de...

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“…Interestingly, just as the inclusions in FTLD-U and ALS are immunoreactive to phosphorylation-specific antibodies toward pS409/S410 (16,21), so are the inclusions formed by the 25-kDa fragments (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity

Zhang

Cook

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining histopathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a Ϸ25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin-and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.caspase ͉ inclusion ͉ amyotrophic lateral sclerosis ͉ cell death ͉ frontotemporal lobar degeneration with ubiquitin-positive inclusions

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Abnormal phosphorylation of Ser409/410 of TDP‐43 in FTLD‐U and ALS

Cited by 176 publications

References 22 publications

Multiplex SILAC Analysis of a Cellular TDP-43 Proteinopathy Model Reveals Protein Inclusions Associated with SUMOylation and Diverse Polyubiquitin Chains

Multiplex SILAC Analysis of a Cellular TDP-43 Proteinopathy Model Reveals Protein Inclusions Associated with SUMOylation and Diverse Polyubiquitin Chains

Rapamycin Rescues TDP-43 Mislocalization and the Associated Low Molecular Mass Neurofilament Instability

Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity

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