Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by CAG/polyglutamine expansion in the androgen receptor (AR) gene.
• Skeletal muscle is a key tissue affected in SBMA, exhibiting degenerative changes.

Purpose of the Study:

• To investigate molecular pathways disrupted in skeletal muscle of SBMA using a mouse model.
• To identify the role of the ubiquitin-proteasome system in SBMA pathogenesis.

Main Methods:

• RNA-sequencing (RNA-Seq) was employed to analyze gene expression in AR113Q knockin mice.
• Levels of proteasome components, transcription factors (NRF1, DDI2), and protein aggregation were assessed.

Main Results:

• Diminished expression of ubiquitin/proteasome pathway genes was observed in AR113Q muscle.
• Decreased NRF1 and DDI2 levels led to reduced proteasome activity and accumulation of ubiquitinated proteins (ADRM1).
• Proteasome dysfunction was dependent on age, hormone levels, and polyglutamine tract length.

Conclusions:

• AR113Q muscle exhibits progressive proteasome dysfunction, impairing cellular quality control.
• This dysfunction contributes to the accumulation of polyglutamine AR protein and the age-dependent progression of SBMA.