Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Ribosomes are essential molecular machines for protein synthesis.
• Reduced ribosomal protein gene dosage causes human ribosomopathies.
• The cellular basis of ribosomopathies is poorly understood.

Purpose of the Study:

• To investigate the cell biological underpinnings of ribosomopathies.
• To identify potential therapeutic targets for ribosomopathies.

Main Methods:

• Modeling human ribosomopathies in Drosophila.
• Assessing apoptosis, cellular stress, and protein degradation pathways.
• Investigating the role of the integrated stress response and autophagy.
• Examining the effects of TOR pathway inhibition.

Main Results:

• Ribosomal protein deficiency in Drosophila models leads to apoptosis and cellular stress.
• Proteotoxic stress, due to misfolded protein accumulation, is the primary pathology, not insufficient protein synthesis.
• The integrated stress response and autophagy appear cytoprotective.
• Inhibition of TOR activity reduces proteotoxic stress.

Conclusions:

• Ribosomopathies are characterized by proteotoxic stress rather than impaired protein synthesis.
• Therapeutic strategies may involve stimulating autophagy and enhancing protein quality control.
• Targeting the TOR pathway could be beneficial for treating ribosomopathies.