DNA binding and mitotic phosphorylation protect polyglutamine proteins from assembly formation

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Polyglutamine (polyQ) expansion causes protein aggregation in neurodegenerative diseases.
• Long polyQ tracts are also present in transcription factors (TFs), including FOXP2, crucial for human speech.
• Understanding how these TFs avoid aggregation is vital.

Purpose of the Study:

• To investigate the mechanisms preventing aggregation in glutamine-rich transcription factors, specifically FOXP2.
• To explore the role of DNA binding and phosphorylation in maintaining TF solubility.
• To examine how human-specific mutations in FOXP2 affect its assembly propensity.

Main Methods:

• Studied FOXP2 and other glutamine-rich TFs during interphase and mitosis.
• Investigated the effect of DNA binding on TF solubility.
• Analyzed the impact of phosphorylation events on FOXP2 chromatin binding and solubility.
• Examined human-specific amino acid substitutions in FOXP2 and their effect on assembly.
• Tested strategies to reduce Huntingtin assembly using DNA-binding domains, phosphomimetic variants, or charged peptides.

Main Results:

• DNA binding generally increases the solubility of TFs during interphase.
• Mitotic phosphorylation causes FOXP2 eviction from chromatin, replacing the solubilizing effect of DNA.
• Human-specific substitutions in FOXP2's 'EVO patch' decrease its aggregation propensity.
• Modifying Huntingtin with DNA-binding, phosphomimetic, or charged peptides reduces its assembly.

Conclusions:

• Solubility of glutamine-rich TFs is regulated by DNA binding and phosphorylation.
• Human-specific evolution of FOXP2 involved changes that reduce aggregation.
• Targeting mechanisms that control TF solubility may offer novel therapeutic approaches for polyQ expansion diseases.