N-terminal polyglutamine-containing fragments inhibit androgen receptor transactivation function

Area of Science:

• Neurobiology
• Molecular Biology
• Genetics

Background:

• Neurodegenerative diseases like Kennedy's disease (KD) involve misfolded polyglutamine (polyQ) proteins.
• KD stems from polyQ expansion in the androgen receptor (AR), impacting male development and causing androgen insensitivity syndrome (AIS).

Purpose of the Study:

• To investigate the molecular mechanisms underlying AIS in KD using a yeast model.
• To elucidate how polyQ-expanded AR fragments contribute to AR dysfunction.

Main Methods:

• Expressed polyQ-expanded N-terminal AR fragments in yeast Saccharomyces cerevisiae.
• Assessed polyQ length-dependent toxicity and protein aggregation.
• Utilized a hormone-dependent luciferase reporter assay to measure AR transactivation activity.

Main Results:

• PolyQ-expanded AR fragments induced length-dependent growth defects in yeast.
• AR fragments with 102 Qs formed soluble oligomers, showing higher toxicity than aggregated forms.
• Soluble polyQ-AR fragments inactivated full-length AR, with maximal impairment observed upon interaction.

Conclusions:

• Soluble polyQ-containing AR fragments bind to and inactivate full-length AR.
• This interaction provides a molecular basis for AIS in KD.
• The findings offer insights into pathogenic mechanisms in other polyglutamine diseases like Huntington's disease.