Protein Arginine Methyltransferase 6 Enhances Polyglutamine-Expanded Androgen Receptor Function and Toxicity in Spinal and Bulbar Muscular Atrophy

Summary

Polyglutamine expansion in androgen receptor (AR) is responsible for spinobulbar muscular atrophy (SBMA) that leads to selective loss of lower motor neurons. Using SBMA as a model, we explored the relationship between protein structure/function and neurodegeneration in polyglutamine diseases. We show here that protein arginine methyltransferase 6 (PRMT6) is a specific co-activator of normal and mutant AR and that the interaction of PRMT6 with AR is significantly enhanced in the AR mutant. AR and PRMT6 interaction occurs through the PRMT6 steroid receptor interaction motif, LXXLL, and the AR activating function 2 surface. AR transactivation requires PRMT6 catalytic activity and involves methylation of arginine residues at Akt consensus site motifs, which is mutually exclusive with serine phosphorylation by Akt. The enhanced interaction of PRMT6 and mutant AR leads to neurodegeneration in cell and fly models of SBMA. These findings demonstrate a direct role of arginine methylation in polyglutamine disease pathogenesis.

Highlights

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  PRMT6 is a coactivator of AR whose function is enhanced by polyglutamine expansion

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  PRMT6 methylates the AR at the two Akt consensus site motifs RXRXXS

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  AR arginine methylation by PRMT6 and phosphorylation by Akt are mutually exclusive

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  PRMT6 enhances mutant AR toxicity in spinobulbar muscular atrophy cells and flies

Abstract

The relationship between polyglutamine protein structure/function and neurodegeneration is poorly understood. Using SBMA as a model of polyglutamine diseases, Scaramuzzino et al. show that protein arginine methyltransferase 6 enhances polyglutamine androgen receptor function and toxicity through direct modification of the disease protein.