Two German Kindreds With Familial Amyotrophic Lateral Sclerosis Due to TARDBP Mutations

Kühnlein, Peter; Sperfeld, Anne‐Dorte; Vanmassenhove, Ben; Deerlin, Vivianna M. Van; Lee, Virginia M.‐Y.; Trojanowski, John Q.; Kretzschmar, Hans A.; Ludolph, Albert C.; Neumann, Manuela

doi:10.1001/archneur.65.9.1185

Cited by 141 publications

(105 citation statements)

References 18 publications

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“…Ubiquitinated TDP-43 is especially prevalent in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). In these diseases, many mutations have been identified within the glycine-rich region (GRR) of TDP-43 (ϳ30 mutations in ALS [37,48,51,63,66,69,72] and 2 in FTLD-U [14,21,38,46]). How TDP-43 contributes to neurodegeneration is not known, but other pathological alterations to TDP-43 implicate aberrant proteolysis, hyperphosphorylation, and misaccumulation in the cytoplasm (7,16,21,35,59).…”

mentioning

confidence: 99%

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

Dewey

Cenik

Sephton

et al. 2011

Molecular and Cellular Biology

297

306

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TDP-43, or TAR DNA-binding protein 43, is a pathological marker of a spectrum of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinpositive inclusions. TDP-43 is an RNA/DNA-binding protein implicated in transcriptional and posttranscriptional regulation. Recent work also suggests that TDP-43 associates with cytoplasmic stress granules, which are transient structures that form in response to stress. In this study, we establish sorbitol as a novel physiological stressor that directs TDP-43 to stress granules in Hek293T cells and primary cultured glia. We quantify the association of TDP-43 with stress granules over time and show that stress granule association and size are dependent on the glycine-rich region of TDP-43, which harbors the majority of pathogenic mutations. Moreover, we establish that cells harboring wild-type and mutant TDP-43 have distinct stress responses: mutant TDP-43 forms significantly larger stress granules, and is incorporated into stress granules earlier, than wild-type TDP-43; in striking contrast, wild-type TDP-43 forms more stress granules over time, but the granule size remains relatively unchanged. We propose that mutant TDP-43 alters stress granule dynamics, which may contribute to the progression of TDP-43 proteinopathies.TAR DNA-binding protein 43 (TDP-43) is a highly conserved, ubiquitously expressed RNA-binding protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family (11,47,73). TDP-43 and other hnRNPs are multifunctional proteins that regulate gene expression in both the nucleus and the cytoplasm (47, 75). In the nucleus, TDP-43 binds singlestranded DNA and RNA (10,11,19,20,49,62) and can function as both a transcriptional repressor (1, 2, 62) and a splicing modulator (15,17,20,55). Specifically, TDP-43 regulates pre-mRNA splicing by binding mRNA with (UG) 6-12 sequences (19) and by recruiting other hnRNP proteins into repressive splicing complexes (10,18,55). However, as a nucleocytoplasmic shuttling protein (12), TDP-43 also has distinct cytoplasmic functions, including mRNA stabilization (74).Recent studies indicate that TDP-43 localizes to stress granules (SGs) in response to heat shock, oxidative stress, and chemical inducers of stress (23,33). SGs are dynamic cytoplasmic structures that are believed to act as sorting stations for mRNAs (5). SG composition and morphology differ according to stress and cell type (5, 39), but some core components are conserved. These core components include the RNA-binding protein TIAR (TIA-1 cytotoxic granule-associated RNA-binding protein-like 1) and the stalled translation initiation complex components eIF3 and eIF4G (44,45). In contrast, the incorporation of the RNA-binding proteins HuR and hnRNP A1 into SGs differs with the cell type and stress (5, 39). The physiological stressors that cause TDP-43 aggregates and SGs to form-and the cells in which this occurs-remain unresolved. Moreover, very little is known about the function of cytoplasmic TDP-43, a press...

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mentioning

confidence: 99%

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

Dewey

Cenik

Sephton

et al. 2011

Molecular and Cellular Biology

297

306

View full text Add to dashboard Cite

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“…However, Sreedharan and colleagues identified mutations in exon 6 of TARDBP in two familial and two sporadic cases (20). This was supported by further studies identifying mutations in exon 6 in both familial and sporadic disease (21)(22)(23)(24)(25). The aim of the present study was to determine the frequency of TARDBP mutations in our large cohort of MND patients from the North of England and to establish the clinical phenotype associated with these mutations.…”

Section: Introductionmentioning

confidence: 63%

“…Bulbar function also remained intact in these individuals. In a previously reported mutation affecting this amino acid it was also commented that there was a lack of bulbar symptoms (22). A paucity of upper motor neurone signs has been described with other mutations (21).…”

Section: Broad Clinical Als Phenotypes Are Associated With Tardbp Mutmentioning

confidence: 95%

“…The familial p.Gly348Val mutation is a novel substitution, though p.Gly348Cys has been reported in four SALS cases from France, two cases in a family from Germany and in a large multigenerational family from Belgium (21,22,26,27). In FALS2 the phenotype observed was predominantly lower motor neurone, with only subtle upper motor neurone changes consisting of retained reflexes in the context of wasting.…”

Section: Broad Clinical Als Phenotypes Are Associated With Tardbp Mutmentioning

confidence: 99%

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Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

et al. 2009

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(Max 150 words)The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the TARDBP gene, encoding TDP-43. All but one are in exon 6, which encodes the glycinerich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease (MND) patients from Northern England (42 non-SOD1 FALS, 9 ALS-FTD, 474 SALS, 45 PMA cases). We identified 4 mutations, 2 of which were novel, in 2 familial (FALS) and 2 sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction.

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“…More than 10 mutations in TARDBP have been identified in FALS and SALS cases (3)(4)(5)(6)(7)(8)(9)(10) (3).…”

Section: Discussionmentioning

confidence: 99%

Familial ALS with G298S Mutation in TARDBP: A Comparison of CSF Tau Protein Levels with those in Sporadic ALS

et al. 2010

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We report a 52-year-old Japanese man showing both upper and lower motor neuron signs with familial amyotrophic lateral sclerosis (ALS). Analysis of the TAR DNA-binding protein of 43 kDa (TDP-43) gene (TARDBP) revealed a glycine-to-serine substitution at position 298 (G298S). Cerebrospinal fluid (CSF) level of total tau protein (CSF-tau) of our patient was found to be highly elevated compared with those of sporadic ALS cases and controls. The elevated CSF-tau level might be related to the damage of neurons exhibiting a large number of TDP-43 inclusions in familial ALS with this mutation.

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Two German Kindreds With Familial Amyotrophic Lateral Sclerosis Due to TARDBP Mutations

Cited by 141 publications

References 18 publications

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

Familial ALS with G298S Mutation in TARDBP: A Comparison of CSF Tau Protein Levels with those in Sporadic ALS

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