Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion

Area of Science:

• Neurobiology
• Molecular Biology
• Cell Biology

Background:

• TDP-43 protein dysregulation is implicated in neurodegenerative diseases.
• Extrinsic stressors can act as a
• second hit
• in disease pathogenesis.
• TDP-43 undergoes reversible nuclear condensation in stressed cells.

Purpose of the Study:

• To investigate the nature of stress-inducible TDP-43 nuclear condensates.
• To determine the role of TDP-43 condensation in cellular function and neurodegeneration.
• To examine the impact of ALS-linked mutations on TDP-43 condensation.

Main Methods:

• Confocal nanoscanning assay to analyze TDP-43 condensation.
• Biochemical assays to study TDP-43 oligomerization, ATP dependence, and RNA interactions.
• Analysis of splicing changes and protein depletion, focusing on STMN2 RNA and protein.

Main Results:

• Stress-inducible TDP-43 condensates are RNA-depleted, non-liquid assemblies requiring TDP-43 oligomerization and ATP.
• RNA inhibits the formation of these condensates.
• ALS-linked mutations alter stress-induced TDP-43 condensation by affecting its affinity to ribonucleoprotein assemblies.
• Nuclear condensation transiently inactivates TDP-43, leading to loss of protein interactions and impaired splicing, notably affecting STMN2 RNA and protein levels.

Conclusions:

• Stress-induced nuclear TDP-43 condensation represents an early pathological event in neurodegeneration.
• These condensates lead to functional deficits, including altered splicing.
• Modulating cellular stress responses may offer a therapeutic strategy for ALS.