Enrichment of C-Terminal Fragments in TAR DNA-Binding Protein-43 Cytoplasmic Inclusions in Brain but not in Spinal Cord of Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Igaz, Lionel M.; Kwong, Linda K.; Xu, Yan; Truax, Adam C.; Uryu, Kunihiro; Neumann, Manuela; Clark, Christopher M.; Elman, Lauren; Miller, Bruce L.; Grossman, Murray; McCluskey, Leo; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.2353/ajpath.2008.080003

Cited by 298 publications

(276 citation statements)

References 39 publications

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“…However, the extent of the contribution of these C-terminal fragments to disease pathogenesis is undetermined. Indeed, double-immunofluorescent labeling of ALS patient spinal cords using N-terminalspecific and C-terminal-specific antibodies suggests that inclusions in spinal cord motor neurons are comprised primarily of full-length TDP-43 (37). Importantly, retention of ability to bind RNA by fulllength TDP-43 has been demonstrated to be required for toxicity in yeast, fly, and Caenorhabditis elegans models (43)(44)(45)(46).…”

Section: Significancementioning

confidence: 99%

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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.

414

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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Section: Significancementioning

confidence: 99%

“…ALS and FTLD-U patient brain and spinal cord samples are characterized by the accumulation of cytoplasmic TDP-43 aggregates accompanied by a distinct clearing of nuclear TDP-43 within affected neurons and glia (36,37), implicating possible loss of nuclear TDP-43 function in disease pathogenesis. In human…”

mentioning

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.

414

419

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“…TDP-43 is ubiquitously expressed and has been implicated to play a functional role in many RNA processes, including gene transcription, splicing, mRNA processing, and mRNA stability (6 -8). TDP-43 is localized in the nucleus in normal cells but redistributes to form cytoplasmic aggregates composed of hyperphosphorylated and ubiquitinated C-terminal fragments in diseased cells (9). As inferred from studies of other protein aggregates involved in neurodegenerative diseases (10), TDP-43 aggregates may arise from the population of non-native conformations that probably drive the neurodegeneration directly through a gain-of-function or loss-of-function mechanism.…”

mentioning

confidence: 99%

Folding of the RNA Recognition Motif (RRM) Domains of the Amyotrophic Lateral Sclerosis (ALS)-linked Protein TDP-43 Reveals an Intermediate State

Mackness

Tran

McClain

et al. 2014

Journal of Biological Chemistry

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“…In addition, TDP-43 seems to be ubiquitinylated, phosphorylated, and fragmented in pathological conditions (3). Transient expression of TDP-43 fragments in mammalian cell lines and yeast have led to a widely held view that the C-terminal fragment of TDP-43 is extremely toxic (22,23), although it remains unresolved how C-terminal fragments are generated under physiological or pathological conditions (24,25 (Fig. 1).…”

mentioning

confidence: 99%

ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS

Ling

Albuquerque²,

Han

et al. 2010

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

404

382

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Dominant mutations in two functionally related DNA/RNA-binding proteins, trans-activating response region (TAR) DNA-binding protein with a molecular mass of 43 KDa (TDP-43) and fused in sarcoma/ translocation in liposarcoma (FUS/TLS), cause an inherited form of ALS that is accompanied by nuclear and cytoplasmic aggregates containing TDP-43 or FUS/TLS. Using isogenic cell lines expressing wild-type or ALS-linked TDP-43 mutants and fibroblasts from a human patient, pulse-chase radiolabeling of newly synthesized proteins is used to determine, surprisingly, that ALS-linked TDP-43 mutant polypeptides are more stable than wild-type TDP-43. Tandem-affinity purification and quantitative mass spectrometry are used to identify TDP-43 complexes not only with heterogeneous nuclear ribonucleoproteins family proteins, as expected, but also with components of Drosha microprocessor complexes, consistent with roles for TDP-43 in both mRNA processing and microRNA biogenesis. A fraction of TDP-43 is shown to be complexed with FUS/TLS, an interaction substantially enhanced by TDP-43 mutants. Taken together, abnormal stability of mutant TDP-43 and its enhanced binding to normal FUS/TLS imply a convergence of pathogenic pathways from mutant TDP-43 and FUS/TLS in ALS.mass spectrometry | protein stability | amyotrophic lateral sclerosis | microRNA | ribonucleoproteins

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Enrichment of C-Terminal Fragments in TAR DNA-Binding Protein-43 Cytoplasmic Inclusions in Brain but not in Spinal Cord of Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Cited by 298 publications

References 39 publications

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

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

Folding of the RNA Recognition Motif (RRM) Domains of the Amyotrophic Lateral Sclerosis (ALS)-linked Protein TDP-43 Reveals an Intermediate State

ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS

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