The involvement of tau in nucleolar transcription and the stress response

Abstract

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.

Decreased synthesis of ribosomal proteins in tauopathy revealed by non‐canonical amino acid labelling

“…Our results further support the emerging hypothesis that tau affects components of the translational machinery and that this regulation is altered in disease (Li & Götz, ). Tau has been shown to interact with several components of the translational machinery, including nuclear, ribosomal and RNA‐binding proteins (Meier et al , ; Vanderweyde et al , ; Maina et al , ). We have previously demonstrated that amyloid‐β induces increased de novo synthesis of tau through an activation of a signalling cascade that involves the Src kinase Fyn, the serine/threonine‐directed kinase ERK and the ribosomal protein S6 (Li & Götz, ).…”

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

“…This seems to suggest that the protein synthesis machinery becomes altered before the onset of AD and this progresses with the disease process. Interestingly, tau has been shown to play a role in the nucleus and nucleolus as well as being a microtubule binding protein in the cytosol ( Maina et al, 2018 ).…”

Altered Levels and Isoforms of Tau and Nuclear Membrane Invaginations in Huntington’s Disease

“…DNA binding of Tau takes place at both genic and intergenic regions (Benhelli-Mokrani et al, 2018) and results in modulation of gene expression (Siano et al, 2019). Interestingly, nuclear Tau has also been involved in nucleolar transcription (Maina et al, 2018) and the decrease in nuclear Tau (detected with Tau-100 antibody) that takes place in AD CA1 and dentate gyrus neurons along disease progression might be pathogenic by leading to decreased protein synthesis (Hernández-Ortega et al, 2016). Finally, different mutations that alter the proportion of Tau isoforms as well as post-translational modifications can modify the affinity of Tau for microtubules.…”