Altered ribosomal function and protein synthesis caused by tau.

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Protein synthesis is crucial for neurological functions, including memory.
• Protein synthesis is impaired in neurodegenerative diseases like tauopathies, involving the microtubule-associated protein tau.
• Frontotemporal dementia (FTD) is a tauopathy where mutant tau impairs cellular processes.

Purpose of the Study:

• To comprehensively analyze the impact of FTD-associated mutant tau on ribosomes and protein synthesis.
• To identify specific ribosomal alterations in FTD mouse models.
• To elucidate the role of tau in ribosomal dysfunction.

Main Methods:

• Polysome profiling
• De novo protein labeling
• Mass spectrometry-based proteomics
• Primary neuronal cultures from FTD mouse models

Main Results:

• Ten ribosomal proteins (RPs) were decreased in abundance in primary neurons from an FTD mouse model.
• Expression of human tau (hTau) reduced protein synthesis and 60S ribosomal subunit biogenesis.
• FTD-associated tau mutations exacerbated these inhibitory effects on protein synthesis and ribosomal biogenesis.
• The amino-terminal projection domain of hTau alone was sufficient to impair protein synthesis and ribosomal biogenesis.

Conclusions:

• Aberrant tau, particularly FTD-associated mutations, significantly impairs ribosome function and protein synthesis.
• Tau directly impacts ribosomal biogenesis, specifically affecting the 60S subunit.
• These findings reinforce tau's role in cellular dysfunction in neurodegenerative conditions like FTD.