Tau drives translational selectivity by interacting with ribosomal proteins

Abstract

There is a fundamental gap in understanding the consequences of tau–ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and found that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis under translational control of rpS6 was reduced under tauopathic conditions in Alzheimer’s disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, since regulation of protein synthesis is critical for learning and memory, aberrant tau–ribosome interactions in disease could explain the linkage between tauopathies and cognitive impairment.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-01970-9) contains supplementary material, which is available to authorized users.

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

“…Interestingly, in Tau R406W flies we note an ~18% increase in agingassociated transcripts, with 7,970 genes affected (versus 6,742 in controls). However, within the proteome, the reverse pattern is seen with only 258 age-associated protein changes detected (versus 1,155 in controls), representing a 78% reduction, and potentially consistent with reports of Tau-induced translational dysregulation [40][41][42]. A similar trend for the proteome is observed in Tau WT animals; although, the magnitude of changes was more modest (Additional File 2: Table S3).…”

“…Though further investigation is warranted to confirm these observations, our analyses define Tau expression signatures in the both transcriptome and proteome enriched for genes implicated in translation, including numerous ribosomal proteins. Consistent with this, pathologic forms of Tau have been shown to avidly bind ribosomal proteins and disrupt their function [40][41][42].…”

“…Prior studies have profiled brain gene expression in Tau transgenic animals, including in flies [31,32,52] and mouse models [21,23,41]; however, none to our knowledge have longitudinally assessed both transcripts and proteins in parallel. Our analyses provide a glimpse of the dynamic regulatory crosstalk between the brain transcriptome and proteome that respond to brain injury, as in tauopathy.…”

Tau protein- induced sequestration of the eukaryotic ribosome: Implications in neurodegenerative disease

“…No significant change in GFP activity was observed in presence of equivalent amounts of the native BCAII protein. Earlier studies had also indicated that the tau protein might possess the ability to modulate the translation process 4,26 . Hence the translational suppression in presence of the tau protein variants implies that the loss of physical integrity of the ribosomal population (as observed by change in A 260 nm profile in Fig.…”

Donor specific transcriptomic analysis of Alzheimer’s disease associated hypometabolism highlights a unique donor, microglia, and ribosomal proteins

“…The ribosome and protein synthesis have been previously associated with mild cognitive impairment and AD (Ding et al, 2005;Hernández-Ortega et al, 2016;Langstrom et al, 1989;Sajdel-Sulkowska and Marotta, 1984) . Pathological tau has also been shown to determine translational selectivity and co-localize with ribosomes (Koren et al, 2019;Meier et al, 2016) . P. gingivalis DNA promotes aggregation of tau (Tetz et al, 2020) , and it has been postulated that tau fibrillization may block cytoskeleton-trafficking infections agents (Moir et al, 2018) .…”