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ePoster
THE ALTERNATIVE ANDROGEN RECEPTOR ISOFORM A MITIGATES TOXICITY OF POLYGLUTAMINE-ELONGATED MUTANT ANDROGEN RECEPTOR IN SPINAL AND BULBAR MUSCULAR ATROPHY
Marta Chierichettiand 18 co-authors
University of Milan
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS02-07PM-407
Presentation
Date TBA
Board: PS02-07PM-407
Event Information
Poster Board
PS02-07PM-407
Poster
View posterAbstract
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a CAG-repeat expansion in the androgen receptor (AR) gene, translated into an elongated polyglutamine (polyQ) tract in the protein. Androgens trigger ARpolyQ toxicity, thus most potential therapeutic approaches involve androgen reduction or AR negative modulation, with severe endocrine side effects. A start codon (I-AUG) controls AR translation, while a second one, (II-AUG) downstream to I-AUG and the CAG repeat, drives translation of the shorter AR isoform (AR-A) lacking the polyQ tract, but preserves all relevant AR functional domains. Comparative expression analyses of AR isoforms revealed that AR-A is predominantly located in the mouse brainstem and spinal cord of the central nervous system. AR-A retains partial androgenic activity, but does not aggregate. Since ARpolyQ and AR-A can heterodimerize, we tested the effect of AR-A on ARpolyQ behaviour, showing that AR-A has a pro-solubilizing effect on ARpolyQ aggregates and that retain a partial transcriptional activity. Finally, we tested the effect of AR-A in a fly model of SBMA. Flies expressing AR-A showed no signs of external eye degeneration, in contrast to those expressing expanded ARpolyQ. Notably, co-expression of AR-A with ARpolyQ reduced ARpolyQ aggregation and eye degeneration, supporting our hypothesis that AR-A enhances ARpolyQ solubility and mitigates its toxicity. Altogether, our results demonstrate that an increased expression of AR-A may have a role in protecting against ARpolyQ aggregation and toxicity. These findings suggest that AR-A could represent a promising avenue for developing an alternative therapeutic strategy that warrants further investigation.
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