TDP-43 binds to RNA G-quadruplex structure and regulates mRNA stability and translation.

Area of Science:

• Molecular Biology
• Neuroscience
• RNA Biology

Background:

• TDP-43 is a key protein in neurodegenerative diseases.
• TDP-43 interacts with RNA G-quadruplexes (rG4s), affecting mRNA.
• Specific TDP-43-rG4 interactions and their functional impact remain unclear.

Purpose of the Study:

• Investigate TDP-43's binding preference for rG4 structures.
• Determine TDP-43's role in global mRNA structural changes.
• Elucidate TDP-43's regulation of specific RNA targets, like SLC1A5.

Main Methods:

• High-throughput RNA bind-n-seq to identify rG4 binding.
• SHALiPE-seq to assess transcriptome-wide mRNA structure.
• Transcript-specific analysis of TDP-43 binding and rG4 function.

Main Results:

• TDP-43 preferentially binds rG4 structures under K+ conditions.
• TDP-43 loss decreases global mRNA structure, particularly in 3'UTRs.
• TDP-43 binds the 3'UTR rG4 of SLC1A5, enhancing its stability and translation.

Conclusions:

• TDP-43 regulates mRNA structure and function through rG4 interactions.
• rG4 structures are crucial for TDP-43-mediated gene regulation.
• Findings provide insights into TDP-43's role in disease and potential therapeutic avenues.