Tau protein binds to pericentromeric DNA: a putative role for nuclear tau in nucleolar organization

Sjöberg, Marcela; Shestakova, Elena; Mansuroglu, Zeyni; Maccioni, Ricardo B.; Bonnefoy, Eliette

doi:10.1242/jcs.02907

Cited by 141 publications

(160 citation statements)

References 74 publications

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“…Nuclear tau has been localized to nucleoli and to the nucleolar organizing regions (NORs) where it may have a role in the synthesis and transcription of rRNA [5,31]. A putative role is also in nucleolar organization by binding to pericentromeric DNA [14]. The punctate pattern seen for Tau-1 in our immunocytochemical study in SH-SY5Y cells is reminiscent of that of nucleoli although this has not been further investigated.…”

Section: Discussionmentioning

confidence: 78%

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Visualizing the microtubule-associated protein tau in the nucleus

Lü

et al. 2014

Sci. China Life Sci.

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Although tau is mainly known as an axonal microtubule-associated protein, many studies indicate that it is not restricted to this subcellular compartment. Assessing tau's subcellular distribution, however, is not trivial as is evident from transgenic mouse studies. When human tau is over-expressed, it can be immunohistochemically localized to axons and the somatodendritic domain, modeling what is found in neurodegenerative diseases such as Alzheimer's disease. Yet, in wild-type mice, despite its abundance, tau is difficult to visualize even in the axon. It is even more challenging to detect this protein in the nucleus, where tau has been proposed to protect DNA from damage. To establish a framework for future studies into tau's nuclear functions, we compared several methods to visualize endogenous nuclear tau in cell lines and mouse brain. While depending on the fixation and permeabilization protocol, we were able to detect nuclear tau in SH-SY5Y human neuroblastoma cells, we failed to do so in N2a murine neuroblastoma cells. As a second method we used subcellular fractionation of mouse tissue and found that in the nucleus tau is mainly present in a hypophosphorylated form. When either full-length or truncated human tau was expressed, both accumulated in the cytoplasm, but were also found in the nuclear fraction. Because subcellular fractionation methods have their limitations, we finally isolated nuclei to probe for nuclear tau and found that the nuclei were free of cytoplasmic contamination. Together our analysis identifies several protocols for detecting tau in the nucleus where it is found in a less phosphorylated form.

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Section: Discussionmentioning

confidence: 78%

“…Method III [14]. The cells were first fixed with 1% PFA for 20 min, and then with methanol for 10 min.…”

mentioning

confidence: 99%

Visualizing the microtubule-associated protein tau in the nucleus

Lü

et al. 2014

Sci. China Life Sci.

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“…Our data fit a model in which an enzymatic product of XDH is transported by White and Brown into granules and in which interaction of this product with tau is detrimental to the cell. Drosopterins are derived from the nucleotide guanosine-59-triphosphate (GTP), and it has been demonstrated that mammalian tau can interact directly with nucleic acids (Schrö der et al 1984;Wang et al 2006;Sjö berg et al 2006); thus it is conceivable that nucleotides and derivatives such as drosopterins directly interact with tau and induce aggregation. This association could also sterically inhibit the interaction of kinases with tau, causing a reduction of AT8 signal.…”

Section: /Wmentioning

confidence: 99%

Interaction Between Eye Pigment Genes and Tau-Induced Neurodegeneration inDrosophila melanogaster

Ambegaokar

Jackson

2010

Genetics

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Null mutations in the genes white and brown, but not scarlet, enhance a rough eye phenotype in a Drosophila melanogaster model of tauopathy; however, adding rosy mutations suppresses these effects. Interaction with nucleotide-derived pigments or increased lysosomal dysregulation are potential mechanisms. Finally, tau toxicity correlates with increased GSK-3b activity, but not with tau phosphorylation at Ser202/Thr205.

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“…Using the Tau1 antibody directed against a non-phosphorylated epitope of Tau protein (serine 195-202), differences in the sub-nuclear localization of Tau have been observed between human and murine cells. In human brain and interphase non-neuronal cells, the Tau1 antibody detects a unique nucleolar localization of Tau (24,26,28), whereas a diffuse Tau1 labeling is observed in murine neuronal cells (27).…”

Section: Possible Sources Of Nuclear Aicd A␤ and Taumentioning

confidence: 99%

“…Tau has been reported to bind single-and double-stranded DNA via the minor groove (26,27,84,85), thereby drawing parallels between Tau and histones in terms of DNA binding. Indeed, monomers or small oligomers of Tau can bind to DNA complexes and give rise to a "beads-on-a-string" organization like histone-DNA assembly (80,84), thus suggesting that Tau could act like a chaperone (26,27,84). Although larger aggregates of Tau interact only weakly with DNA (84,86), complexes between large Tau aggregates and DNA have been observed in vitro, suggesting that different Tau-DNA structures exist (84).…”

Section: Aicd A␤42 and Tau Interactions With Dnamentioning

confidence: 99%

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

Multhaup

Huber

Buée

et al. 2015

Journal of Biological Chemistry

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Alzheimer disease (AD) 2 is the most common form of dementia and a leading cause of death. Amyloid-␤ (A␤) peptides of varying length (30 -51 amino acid residues) are produced by the sequential, proteolytic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases (1, 2). In the healthy brain, these protein fragments are normally degraded and eliminated. In the AD brain, the 42-amino acid peptide (A␤42) is prone to form aggregated amyloid oligomers, which are believed to contribute to plaque formation and cognitive decline (3-6).The ␥-secretase also liberates an intracellular fragment called AICD composed of up to 50 residues depending on N-terminal variations (7-9). The first identification of the APP intracellular fragment (AICD) and its detection in brain tissue (8) immediately suggested that it has transcriptional activity, like the Notch intracellular domain (NICD). Whether amyloid A␤ represents a biologically inert bypass product of APP processing or can harbor its own function is a leading question in the AD field. A␤ is potentially toxic depending on its biophysical state (10). Equimolar amounts of the A␤ peptides and the C-terminal fragment AICD are derived from the ␤-C-terminal fragment C99 (11), which represents the APP fragment generated by the initial APP cleavage by ␤-secretase (Fig. 1).A seminal discovery concerning the transcriptional regulatory function of the APP cytoplasmic tail was the observation of its complex formation with Fe65 and the histone acetyltransferase Tip60 and transcriptional activity in reporter gene assays (12). Transactivation of transcription requires ␥-secretase activity and nuclear translocation of Fe65 but not of AICD under these assay conditions (13). However, other studies detected AICD in transcriptional complexes on promoters of target genes using ChIP (see below).In addition, there is evidence that soluble APP fragments (sAPP) of the ectodomain can modulate gene transcription in stimulating downstream signaling through unknown sAPP receptor(s) (14). Accumulation of intracellular A␤ species in neuronal cells before plaque formation leading to concomitant loss of MAP2 expression suggested that A␤ may affect expression or turnover of other proteins (15-17). However, it was not clarified whether this occurs at the transcriptional or translational level.Using a variety of techniques, the recently detected uptake of A␤ peptides into the nuclei of cultured cells (as well as in vivo) revealed that A␤42 possesses unique modulatory activity (18). Direct evidence for the presence of (i) nuclear A␤42 in wildtype animals, (ii) the increased level of nuclear A␤42 in APPoverexpressing animals, and (iii) the detection of nuclear A␤ in quantities comparable with other transcription factors imply a certain biological relevance.The second major hallmark of AD pathology is the presence of neurofibrillary tangles and is associated with intracellular Tau aggregates called neurofibrillary tangles and with modified Tau (19). Although the neuronal Tau (tubulin-associated unit...

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Tau protein binds to pericentromeric DNA: a putative role for nuclear tau in nucleolar organization

Cited by 141 publications

References 74 publications

Visualizing the microtubule-associated protein tau in the nucleus

Visualizing the microtubule-associated protein tau in the nucleus

Interaction Between Eye Pigment Genes and Tau-Induced Neurodegeneration inDrosophila melanogaster

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

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