RNA G-quadruplex organizes stress granule assembly through DNAPTP6 in neurons

Area of Science:

• Neuroscience
• Molecular Biology
• RNA Biology

Background:

• Consecutive guanine sequences form RNA G-quadruplexes (rG4s).
• The roles of rG4s in the central nervous system are largely unknown.
• Stress granules (SGs) are cellular compartments involved in stress response.

Purpose of the Study:

• To investigate the function of rG4s in the central nervous system.
• To identify proteins that bind rG4s and their roles in neuronal function.
• To elucidate the mechanism by which rG4s influence stress granule assembly and neuronal health.

Main Methods:

• Proteomics analysis of mouse forebrain.
• RNA binding assays to determine DNAPTP6 affinity and selectivity for rG4s.
• Neuronal cell culture and knockdown experiments to assess the impact of DNAPTP6 on SG formation, synaptic function, and cell viability under oxidative stress.

Main Results:

• Proteomics identified DNAPTP6 as a high-affinity rG4-binding protein.
• DNAPTP6 is essential for rG4-dependent stress granule assembly in neurons.
• DNAPTP6 knockdown impairs SG formation, leading to synaptic dysfunction and neuronal cell death under oxidative stress.
• rG4s recruit mRNAs into SGs via DNAPTP6, promoting RNA self-assembly and protein phase separation.

Conclusions:

• DNAPTP6 plays a critical role in neuronal function by mediating rG4-dependent phase separation and stress granule assembly.
• The rG4-DNAPTP6 interaction is vital for maintaining neuronal homeostasis under stress conditions.
• This study highlights a novel mechanism linking RNA structure, protein phase separation, and neuronal survival.