<i>TARDBP</i> variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea

Kovács, Gábor G.; Murrell, Jill R.; Horvath, Sandor; Haraszti, Laszlo; Majtényi, Katalin; Molnár, Mária Judit; Budka, Herbert; Ghetti, Bernardino; Spina, Salvatore

doi:10.1002/mds.22697

Cited by 188 publications

(149 citation statements)

References 20 publications

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“…Mutations in MAPT (Hutton et al 1998;Poorkaj et al 1998;Spillantini et al 1998b), chromosome 9 open reading frame 72 (C9ORF72) (DeJesus-Hernandez et al 2011;Renton et al 2011), and progranulin (GRN) (Baker et al 2006;Cruts et al 2006) are the most common. The other four genes are TARDBP (Benajiba et al 2009;Kovacs et al 2009), FUS (Ticozzi et al 2009), valosin-containing protein (VCP) (Watts et al 2004), and charged multivesicular body protein 2B (CHMP2B) (Skibinski et al 2005).…”

Section: Genetics Of Frontotemporal Dementiamentioning

confidence: 99%

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Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Goedert¹,

Ghetti²,

Spillantini³

2011

Cold Spring Harbor Perspectives in Medicine

138

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Section: Genetics Of Frontotemporal Dementiamentioning

confidence: 99%

“…One patient with a K263E change in TARDBP developed FTD, supranuclear palsy, and chorea, in the absence of MND. Abundant neuronal and glial TDP-43 deposits were in evidence, especially in brainstem and subcortical nuclei (Kovacs et al 2009). The mechanisms by which mutations in TARDBP cause neurodegeneration are unclear.…”

Section: Mutations In Tardbpmentioning

confidence: 99%

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Goedert¹,

Ghetti²,

Spillantini³

2011

Cold Spring Harbor Perspectives in Medicine

138

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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

302

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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“…[15][16][17] The cytoplasmic accumulation of the proteins TDP-43 or FUS, and their link to familial and sporadic forms of ALS and FTLD, demonstrates the existence of common underlying mechanisms in these diseases. 3,[18][19][20][21][22] 26, 28 and 29).…”

Section: Overview Of Als and Ftldmentioning

confidence: 99%