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EMBO J. 2019 Jul 1;38(13):e101174. doi: 10.15252/embj.2018101174. Epub 2019 May 22.

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

Author information

1
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia.
2
New South Wales Brain Bank, The University of Sydney, Sydney, NSW, Australia.

Abstract

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.

KEYWORDS:

neurodegenerative disease; non-canonical amino acid labelling; protein synthesis; ribosomal proteins; tauopathy

PMID:
31268600
PMCID:
PMC6600635
DOI:
10.15252/embj.2018101174
[Indexed for MEDLINE]
Free PMC Article

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