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

• Published in: The EMBO journal 2019-07, Vol.38 (13), p.e101174-n/a
• Main Authors: Evans, Harrison Tudor, Benetatos, Joseph, van Roijen, Marloes, Bodea, Liviu‐Gabriel, Götz, Jürgen
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amino acids; Amyloid; Animal models; Brain; Dementia; Dementia disorders; EMBO27; EMBO32; Frontotemporal dementia; Labeling; neurodegenerative disease; Neurodegenerative diseases; Neurological diseases; non‐canonical amino acid labelling; Protein biosynthesis; Protein synthesis; Proteins; Proteomics; Resource; Ribosomal proteins; Rodents; Scaffolding; Tau protein; tauopathy; Transgenic mice
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2018101174

Tau is a scaffolding protein that serves multiple cellular functions that are perturbed in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). We have recently shown that amyloid‐β, the second hallmark of AD, induces de novo protein synthesis of tau. Importantly, this activation was found to be tau‐dependent, raising the question of whether FTD‐tau by itself affects protein synthesis. We therefore applied non‐canonical amino acid labelling to visualise and identify newly synthesised proteins in the K369I tau transgenic K3 mouse model of FTD. This revealed massively decreased protein synthesis in neurons containing pathologically phosphorylated tau, a finding confirmed in P301L mutant tau transgenic rTg4510 mice. Using quantitative SWATH‐MS proteomics, we identified changes in 247 proteins of the de novo proteome of K3 mice. These included decreased synthesis of the ribosomal proteins RPL23, RPLP0, RPL19 and RPS16, a finding that was validated in both K3 and rTg4510 mice. Together, our findings present a potential pathomechanism by which pathological tau interferes with cellular functions through the dysregulation of ribosomal protein synthesis. Synopsis We demonstrate that protein synthesis is significantly decreased in the presence of frontotemporal dementia tau. Using SWATH‐MS de novo proteomics we reveal altered synthesis of distinct sets of proteins, including ribosomal proteins. Global protein synthesis is decreased in transgenic mouse models of tauopathy and this decrease correlates with tau pathology. SWATH‐MS de novo proteomics shows that distinct clusters of proteins are altered in synthesis in mice with pathological tau. Ribosomal protein synthesis is decreased in two mouse models of tauopathy and this decrease is more pronounced as disease progresses. Total abundance of the ribosomal subunit RPl23 is decreased in mouse models of tauopathy and in human FTD‐brain. Graphical Abstract Analyses of brain samples from transgenic mice and human patients reveal that pathogenic tau alters de novo protein synthesis, suggesting a new mechanism underlying neurodegenerative disease pathology.