Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies

Neumann, Manuela; Kwong, Linda K.; Lee, Edward B.; Kremmer, Elisabeth; Flatley, Andrew; Xu, Yan; Forman, Mark S.; Troost, Dirk; Kretzschmar, Hans A.; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1007/s00401-008-0477-9

Cited by 504 publications

(538 citation statements)

References 42 publications

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“…The demonstration that astrocytes derived from neural stem cells from sporadic ALS patients, but not those from normal controls, mediated motor neuron toxicity suggests that astrocytes participate in pathogenesis of ALS (67). Notably, TDP-43 aggregates in both motor neurons and glial cells are a general hallmark in sporadic ALS (28,29,(68)(69)(70). Together, our results suggest that TDP-43 dysfunction in glial cells contributes to motor neuron degeneration in ALS.…”

Section: Mice Expressing Amir-tdp43 Develop Neurodegeneration In Layer Vmentioning

confidence: 63%

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Yang

Wang

Qiao

et al. 2014

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

152

121

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Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS.

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Section: Mice Expressing Amir-tdp43 Develop Neurodegeneration In Layer Vmentioning

confidence: 63%

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Yang

Wang

Qiao

et al. 2014

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

152

121

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“…Phosphorylated TDP-43 was visualized using a rat mAb that recognizes phosphorylated TDP-43 at serines 409 and 410 (1D3) (26). HA-tagged TEV and GAPDH were visualized with a rat mAb anti-HA (3F10, Roche Applied Science) and mouse anti-GAPDH (Advanced Immunochemical), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…4A). The pathological CTFs extracted from FTLD-TDP brain tissue are heavily phosphorylated and present exclusively in the insoluble fraction (26,35) (Fig. 4A).…”

Section: Nuclear Cleavage Of Tdp-43 Causes Rapid Nuclear Exportmentioning

confidence: 99%

A “Two-hit” Hypothesis for Inclusion Formation by Carboxyl-terminal Fragments of TDP-43 Protein Linked to RNA Depletion and Impaired Microtubule-dependent Transport

Pesiridis¹,

Tripathy²,

Tanik³

et al. 2011

Journal of Biological Chemistry

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100

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Carboxyl-terminal fragments (CTFs) of TDP-43 aggregate to form the diagnostic signature inclusions of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, but the biological significance of these CTFs and how they are generated remain enigmatic. To address these issues, we engineered mammalian cells with an inducible tobacco etch virus (TEV) protease that cleaves TDP-43 containing a TEV cleavage site. Regions of TDP-43 flanking the second RNA recognition motif (RRM2) are efficiently cleaved by TEV, whereas sites within this domain are more resistant to cleavage. CTFs containing RRM2 generated from de novo cleavage of nuclear TDP-43 are transported to the cytoplasm and efficiently cleared, indicating that cleavage alone is not sufficient to initiate CTF aggregation. However, CTFs rapidly aggregated into stable cytoplasmic inclusions following de novo cleavage when dynein-mediated microtubule transport was disrupted, RNA was depleted, or natively misfolded CTFs were introduced into these cells. Our data support a "two-hit" mechanism of CTF aggregation dependent on TDP-43 cleavage.The heterogeneous nuclear ribonucleoprotein (hnRNP) 2 TDP-43 (TAR DNA-binding protein of 43 kDa) forms pathological inclusions that are diagnostic hallmarks of amyotrophic lateral sclerosis (ALS) and the major form of frontotemporal lobar degeneration (FTLD-TDP) (1). Missense mutations in TDP-43 provide a genetic link between hnRNP functions and motor neuron disease (2, 3). TDP-43 is predominantly localized to the nucleus, where it regulates RNA splicing, mRNA stability, microRNA processing, and transcription (4 -6). However, in neurodegenerative TDP-43 proteinopathies like ALS and FTLD-TDP, a loss of nuclear TDP-43 coincides with cytoplasmic TDP-43 inclusions (1). These inclusions contain full-length TDP-43 and TDP-43 C-terminal fragments (CTFs) that are hyperphosphorylated and ubiquitinated. However, it is unclear how each of these species of TDP-43 contributes to inclusion formation or disease pathogenesis.TDP-43 is a typical 2XRRM-gly hnRNP composed of two tandem RNA recognition motifs (RRM1 and RRM2) followed by a glycine-rich carboxyl terminus ( Fig. 1) (7). Both RRMs retain nucleic acid binding properties, yet only RRM1 appears essential for RNA splicing (8). The glycine-rich domain is proposed to interact with other hnRNPs to synergistically affect alternative splicing of specific RNA transcripts (9, 10). A common feature of shuttling hnRNPs involved in RNA splicing is that their nuclear export is coupled to the export and maturation of mRNA in distinct ribonucleoprotein (RNP) complexes (11,12). In this respect, the nucleocytoplasmic shuttling of TDP-43 is dependent on its bipartite importin-␣ nuclear localization signal, a chromosome maintenance region 1 (CRM-1) nuclear export signal in RRM2, and undefined aspects of the carboxyl-terminal glycine-rich domain (13,14).CTFs are signatures of disease exclusively associated with TDP-43 pathology, and CTFs cleaved in the middle of RRM2 extending from amino acid 208 to t...

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“…1073/pnas.1222809110/-/DCSupplemental. disease, TDP-43 has been reported to be abnormally phosphorylated, ubiquitinated, and cleaved to produce C-terminal fragments (4,5,38,39). Ectopic expression of these C-terminal fragments in cell-culture models (40)(41)(42) has shown that they are aggregation-prone and confer an intrinsic toxicity.…”

Section: Significancementioning

confidence: 99%

ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43

Arnold

Ling

Huelga

et al. 2013

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

416

419

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Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43 Q331K and TDP-43 M337V ), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell typeselective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43 Q331K , but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43 Q331K enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage.A myotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are progressive, adult-onset neurodegenerative diseases with overlapping clinical and pathological features (1-3). ALS is characterized by the selective loss of upper and lower motor neurons, leading to progressive fatal paralysis and muscle atrophy. A large majority (∼90%) of ALS and FTLD-U cases are without a known genetic cause. Importantly, in these sporadic cases, the appearance of ubiquitinated inclusions within the affected neurons of the nervous system characterizes both ALS and FTLD-U patients, suggesting an overlapping mechanism underlying both diseases. Biochemical characterization of brains and spinal cords from ALS and FTLD-U patients identified transactivating response region (TAR) DNA binding protein (TDP-43) as the major protein component of these ubiquitinated inclusions (4, 5). The discovery of ALS-linked mutations in the glycine-rich C-terminal domain of TDP-43 (6-8) demonstrated a pathological role of TDP-43 in both diseases. The subsequent identification of mutations in a structurally and functionally related nucleic acid binding protein, FUS/ TLS (fused in sarcoma/translocated in liposarcoma) (9, 10), further implicated defects in RNA processing in ALS pathogenesis.TDP-43 is a multifunctional nucleic acid binding protein.Within the nervous system, TDP-43 binds to >6,000 pre-mRNAs and affects the levels of ∼600 mRNAs and the splicing patterns of another 950 (11). Structura...

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Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies

Cited by 504 publications

References 42 publications

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

A “Two-hit” Hypothesis for Inclusion Formation by Carboxyl-terminal Fragments of TDP-43 Protein Linked to RNA Depletion and Impaired Microtubule-dependent Transport

ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43

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