The Tyr216 phosphorylated form of GSK3β contributes to tau phosphorylation at PHF-1 epitope in response to Aβ in the nucleus of SH-SY5Y cells

Noël, Anastasia; Barrier, Laurence; Ingrand, Sabrina

doi:10.1016/j.lfs.2016.06.020

Cited by 15 publications

(18 citation statements)

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“…Some studies have demonstrated that cellular stress induces the nuclear influx of phosphorylated species of tau and this coincides with cellular and DNA damage [ 24 , 25 , 31 ]. Effects of glutamate stress on nuclear tau phosphorylation were investigated using immunofluorescence microscopy employing Z stacking to enable direct visualisation of the distribution of nuclear tau with DAPI co-fluorescence to allow unbiased quantification of the signals throughout the entire nuclear volume.…”

Section: Resultsmentioning

confidence: 99%

“…A short incubation of cells with 2 mM glutamate also increased both P-Tau and T-Tau nuclear levels, although to lesser extent than with 20 mM glutamate (Additional file 1 : Figure S1D). This shows that the glutamate-induced stress results in an increase in different tau species in the nucleus (nP-Tau and P-Tau), which may impact on nuclear function differently [ 24 , 25 , 31 , 39 ]. Importantly, given that the response observed following both 2 mM and 20 mM Glutamate treatment occured without any changes in total tau levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Non-phosphorylated tau has been found to translocate to the nucleus playing a role in DNA protection during heat stress [ 39 ]. Other reports demonstrate that stress induced by formaldehyde or Aβ42 promotes the nuclear influx of phosphorylated species of tau and this coincides with cellular and DNA damage [ 24 , 25 , 31 ]. These studies suggest that nuclear species of tau may be affected differently depending on the type or severity of the cellular stress.…”

Section: Introductionmentioning

confidence: 99%

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The involvement of tau in nucleolar transcription and the stress response

Maina

Bailey

Wagih

et al. 2018

acta neuropathol commun

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Tau is known for its pathological role in neurodegenerative diseases, including Alzheimer’s disease (AD) and other tauopathies. Tau is found in many subcellular compartments such as the cytosol and the nucleus. Although its normal role in microtubule binding is well established, its nuclear role is still unclear. Here, we reveal that tau localises to the nucleolus in undifferentiated and differentiated neuroblastoma cells (SHSY5Y), where it associates with TIP5, a key player in heterochromatin stability and ribosomal DNA (rDNA) transcriptional repression. Immunogold labelling on human brain sample confirms the physiological relevance of this finding by showing tau within the nucleolus colocalises with TIP5. Depletion of tau results in an increase in rDNA transcription with an associated decrease in heterochromatin and DNA methylation, suggesting that under normal conditions tau is involved in silencing of the rDNA. Cellular stress induced by glutamate causes nucleolar stress associated with the redistribution of nucleolar non-phosphorylated tau, in a similar manner to fibrillarin, and nuclear upsurge of phosphorylated tau (Thr231) which doesn’t colocalise with fibrillarin or nucleolar tau. This suggests that stress may impact on different nuclear tau species. In addition to involvement in rDNA transcription, nucleolar non-phosphorylated tau also undergoes stress-induced redistribution similar to many nucleolar proteins.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0565-6) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The involvement of tau in nucleolar transcription and the stress response

Maina

Bailey

Wagih

et al. 2018

acta neuropathol commun

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“…Incubation of D.SHSY5Y with Aβ42 for 8 h ( Noel et al, 2016 ) or N2a cells with formaldehyde for 2–4 h ( Lu et al, 2013b ), have been shown to result in the accumulation of phosphorylated tau in the nucleus. Therefore, we focussed on the effect of Aβ oligomer incubation for 24 h on the nuclear tau species.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, it seems that different stress signals or kinases could change the cellular activity and behavior of the tau molecule ( Pooler et al, 2012 ; Lu et al, 2013b ). Although recent studies have begun to shed light on how cellular stress impacts on nuclear tau ( Sultan et al, 2011 ; Lu et al, 2013a , b ; Noel et al, 2016 ; Maina et al, 2018 ), how this is affected in AD is not clear. Interestingly, it was recently shown that nuclear tau decreases in both the CA1 and dentate gyrus regions of the AD brain with disease progression ( Hernandez-Ortega et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

The Involvement of Aβ42 and Tau in Nucleolar and Protein Synthesis Machinery Dysfunction

Maina

Bailey

Doherty

et al. 2018

Front. Cell. Neurosci.

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Alzheimer’s disease (AD) is the most common form of dementia and is distinguished from other dementias by observation of extracellular Amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles, comprised of fibrils of Aβ and tau protein, respectively. At early stages, AD is characterized by minimal neurodegeneration, oxidative stress, nucleolar stress, and altered protein synthesis machinery. It is generally believed that Aβ oligomers are the neurotoxic species and their levels in the AD brain correlate with the severity of dementia suggesting that they play a critical role in the pathogenesis of the disease. Here, we show that the incubation of differentiated human neuroblastoma cells (SHSY5Y) with freshly prepared Aβ42 oligomers initially resulted in oxidative stress and subtle nucleolar stress in the absence of DNA damage or cell death. The presence of exogenous Aβ oligomers resulted in altered nuclear tau levels as well as phosphorylation state, leading to altered distribution of nucleolar tau associated with nucleolar stress. These markers of cellular dysfunction worsen over time alongside a reduction in ribosomal RNA synthesis and processing, a decrease in global level of newly synthesized RNA and reduced protein synthesis. The interplay between Aβ and tau in AD remains intriguing and Aβ toxicity has been linked to tau phosphorylation and changes in localization. These findings provide evidence for the involvement of Aβ42 effects on nucleolar tau and protein synthesis machinery dysfunction in cultured cells. Protein synthesis dysfunction is observed in mild cognitive impairment and early AD in the absence of significant neuronal death.

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