A Seeding Reaction Recapitulates Intracellular Formation of Sarkosyl-insoluble Transactivation Response Element (TAR) DNA-binding Protein-43 Inclusions

Furukawa, Yoshiaki; Kaneko, Kazuyuki; Watanabe, Shôji; Yamanaka, Koji; Nukina, Nobuyuki

doi:10.1074/jbc.m111.231209

Cited by 230 publications

(252 citation statements)

References 36 publications

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“…6. In the presence of TDP-43, these polyubiquitinated proteins then could form the TDP-43(ϩ) UBIs with TDP-43 (57,58). To what extent and how generally applicable this proposed scenario is to the ALS cases with TDP-43(ϩ) proteinopathies awaits to be validated in the future.…”

Section: Discussionmentioning

confidence: 99%

Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis-like Phenotypes in Mice

Cheng

Shen

2012

Journal of Biological Chemistry

144

109

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Section: Discussionmentioning

confidence: 99%

Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis-like Phenotypes in Mice

Cheng

Shen

2012

Journal of Biological Chemistry

144

109

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“…Saini et al (26) identified 246 -255 and 311-320 as core aggregation sequences of TDP-43 by evaluating the aggregation ability of a series of peptides derived from the TDP-43 C-terminal sequence (220 -414). Furukawa et al (27)reported that the C-terminal half of TDP-43 (i.e. TDP-432-C) can recapitulate the aggregation propensities of the full-length protein.…”

Section: Discussionmentioning

confidence: 99%

Templated Aggregation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Seeding with TDP-43 Peptide Fibrils

Shimonaka

Nonaka

Suzuki

et al. 2016

Journal of Biological Chemistry

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Frontotemporal lobar degeneration (FTLD)2 is the second most common dementing disorder in patients under 65 years of age and is characterized by progressive atrophy of the frontal and temporal lobes in the brain. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration. In 2006, TAR DNA-binding protein of 43 kDa (TDP-43) was identified as the major component of tau-negative, ubiquitin-positive inclusions in these diseases (1, 2). TDP-43 is a heterogeneous nuclear ribonucleoprotein of 414 amino acids, originally identified as a transcriptional repressor that binds to the transactivation-responsive region of the HIV-1 gene (3). It is expressed ubiquitously and is localized mainly in nuclei, functioning in exon splicing, gene transcription, regulation of mRNA stability and biosynthesis, and the formation of nuclear bodies. For example, it has been reported that TDP-43 binds to the junctional region between exons 9 and 10 of the gene coding cystic fibrosis transmembrane conductance regulator and causes skipping of exon 9 (4). Structurally, TDP-43 is characterized by two RNA-recognition motifs, a C-terminal tail that contains a glycine-rich region and a glutamine/asparagine (Gln/Asn)-rich region.Discovery of missense mutations in the TARBDP gene in patients with familial and sporadic ALS and FTLD (5-12) demonstrated a direct link between genetic lesions and development of TDP-43 pathology. Importantly, most of the mutations are localized in the carboxyl-third of the molecule, which shows sequence similarity to prion proteins. Furthermore, biochemical and histological analyses demonstrated accumulation of full-length and C-terminal fragments (CTFs) in hyperphosphorylated and fibrillar forms in brain and spinal cord of patients (13). Furthermore, the CTF-banding patterns are different between the diseases and are closely related to the neuropathological phenotypes, which can be classified into at least four groups (types A-D) (13,14). The CTF-banding patterns are considered to reflect the protease resistance of the assembled protein structures (15). It was recently demonstrated that the pathological TDP-43 has prion-like activity and can convert normal TDP-43 to an abnormal form in cultured cells (16). Interestingly, the CTF-banding patterns of converted host proteins resemble those of the pathological TDP-43 used as seeds, suggesting that the conversion is template-dependent.These findings strongly suggest that aggregation of C-terminal regions of TDP-43 plays a central role in the pathogenesis and progression of ALS and FTLD with TDP-43 pathologies (FTLD-TDP). The aggregation of CTFs of TDP-43 has also been demonstrated in experimental cellular models; for example, our previous study showed that expression of CTF(162-414) of TDP-43 with a GFP tag in SH-SY5Y cells induced cytosolic mislocalization of TDP-43 in phosphorylated and ubiquitinated aggregates, recapitulating the TDP-43 pathology in brains (17).

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“…Mutations in VCP cause a multisystem proteinopathy consisting of motor neuron disease, frontotemporal dementia, inclusion body myopathy, and Paget's disease of bone [97], suggesting that impaired stress granule dynamics is a conserved thread in these disorders [10,96]. The formation of relatively stable, insoluble foci within the cytoplasm might accelerate self-aggregation of TDP43 and FUS via a prion-like mechanism [98], eventually leading to characteristic skein-like structures or large cytoplasmic inclusions typical of ALS pathology [6].…”

Section: Rna Granulesmentioning

confidence: 99%

“…Recombinant, aggregated TDP43 [98], and insoluble TDP43 isolated from the brains of patients with ALS or FTLD-TDP are capable of inducing TDP43 aggregation and cytotoxicity through a self-templated process in cultured cell lines [98,124]. Propagation of aggregated TDP43 and cell death could be inhibited by treating TDP43 extracts with formic acid, a powerful denaturant, but not by boiling or mild protease treatment, analogous to mammalian prions.…”

Section: Alternative Rna-based Mechanismsmentioning

confidence: 99%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

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The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

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A Seeding Reaction Recapitulates Intracellular Formation of Sarkosyl-insoluble Transactivation Response Element (TAR) DNA-binding Protein-43 Inclusions

Cited by 230 publications

References 36 publications

Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis-like Phenotypes in Mice

Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis-like Phenotypes in Mice

Templated Aggregation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Seeding with TDP-43 Peptide Fibrils

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

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