Long non-coding RNA SNHG8 drives stress granule formation in tauopathies

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Tauopathies are neurodegenerative diseases linked to tau protein aggregation.
• MAPT gene mutations cause some tauopathies, but downstream effects are unclear.
• Long non-coding RNAs (lncRNAs) regulate gene expression and may play a role in tauopathies.

Purpose of the Study:

• Investigate the role of lncRNAs in MAPT mutation-driven tauopathies.
• Identify specific lncRNAs dysregulated in tauopathy.
• Determine the functional relationship between lncRNAs, tau, and stress granule formation.

Main Methods:

• Used patient-derived stem cell neurons with MAPT mutations (P301L, IVS10 + 16, R406W) and CRISPR-corrected controls.
• Performed transcriptomic analysis to identify differentially expressed lncRNAs.
• Investigated interactions between lncRNAs, tau, and RNA-binding proteins (e.g., TIA1).
• Assessed the impact of SNHG8 manipulation on stress granule formation in vitro and in patient-derived neurons.

Main Results:

• Identified 15 lncRNAs commonly altered across three MAPT mutations.
• SNHG8 was significantly reduced in MAPT mutant neurons, a mouse tauopathy model, and human FTLD-tau, PSP, and AD brains.
• SNHG8 interacts with tau and TIA1; mutant tau overexpression reduced SNHG8 and increased stress granules.
• Restoring SNHG8 expression reduced stress granule formation and TIA1 levels.

Conclusions:

• Dysregulation of SNHG8 is a potential causal factor in tauopathy.
• SNHG8 reduction contributes to stress granule formation via TIA1 in MAPT-associated neurodegeneration.
• lncRNAs represent a novel therapeutic target for tauopathies.