Fighting polyglutamine disease by wrestling with SUMO

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Spinobulbar muscular atrophy (SBMA) is an X-linked neurodegenerative disorder.
• It results from polyglutamine (polyQ) expansion in the androgen receptor (AR).
• AR polyQ expansion leads to aggregation and impaired transcriptional activity.

Purpose of the Study:

• To investigate the role of SUMOylation in SBMA pathogenesis.
• To determine if SUMOylation of AR is protective or pathogenic in SBMA.

Main Methods:

• Generation of knockin mouse models expressing polyQ AR or a non-SUMOylatable polyQ AR.
• Assessment of AR transcriptional activity and SBMA-associated phenotypes in mice.

Main Results:

• Inhibiting SUMOylation of polyQ AR restored transcriptional activity.
• Non-SUMOylatable polyQ AR prevented some SBMA symptoms in the mouse model.
• SUMOylation inhibition did not fully resolve all SBMA-associated symptoms.

Conclusions:

• SUMOylation of AR is not protective in SBMA.
• Inhibiting AR SUMOylation may be a therapeutic strategy for SBMA.
• Further research is needed to fully understand the role of SUMOylation in SBMA.