Short Repeat Ribonucleic Acid Reduces Cytotoxicity by Preventing the Aggregation of TDP-43 and Its 25 KDa...

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• TDP-43 proteinopathy is a key feature of neurodegenerative diseases like ALS.
• Cytoplasmic aggregates of TDP-43 and TDP-25 are found in affected neurons.
• Limited research exists on small molecules inhibiting TDP-43 aggregation and toxicity.

Purpose of the Study:

• To identify small molecules that can reduce TDP-43 and TDP-25 aggregation and cytotoxicity.
• To investigate the potential of short RNA repeats as aggregation suppressors.

Main Methods:

• Fluorescence cross-correlation spectroscopy was used to study TDP-25 and TDP-43 interactions with RNA.
• Cellular models were used to assess the effect of GGGGCC and AAAAUU RNA expression on TDP-43 and TDP-25 aggregation.
• Cell death and transcriptome changes were analyzed.

Main Results:

• Short RNA repeats (GGGGCC and AAAAUU) act as aggregation suppressors for TDP-43 and TDP-25.
• TDP-25 interacts with these RNAs, even without canonical RNA-recognition motifs.
• Expression of these RNAs reduced cytoplasmic aggregates and ameliorated cell death without altering chaperone gene expression.

Conclusions:

• Short RNA repeats GGGGCC and AAAAUU can prevent TDP-43 and TDP-25 aggregation.
• These RNAs show potential for maintaining proteostasis in neurodegenerative conditions.
• This study highlights a novel therapeutic strategy targeting protein aggregation.