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.
|Number of pages||13|
|State||Published - Apr 1 2019|
Bibliographical noteFunding Information:
Funding This work was funded by NIH R01NS077284 (HZ) and Alzheimer’s Association NIRG-14-322441, Department of Defense AZ140097, NIH/NIMHD L32 MD009205-01, NIH 1R21NS093440, NIH/NINDS 1R01 NS091329-01 (JFA). Brain samples were obtained from the University of Kentucky ADC, which is supported by NIH/ NIA P30 AG028383. The University of Kentucky Proteomics Core is supported by NIH/NIGMS P20GM103486, NIH/NCI P30CA177558, NIH S10RR029127.
We thank Dr. Peter Nelson,?Ela Patel, and Sonya Anderson, the University of Kentucky Alzheimer?s Disease Center (UK-ADC). We also thank Dr. Steven Estus and James Simpson for their technical support, Dr. Peter Davies for his generous contribution of the PHF1 antibody, and Dr. Chad Dickey for the inspiration for this work and?developing and sharing the iHEK cell lines and the tau plasmids.
© 2019, The Author(s).
- Nascent proteomics
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience