Protein arginine methyltransferase 6 is a modifier of polyglutamine-expanded androgen receptor toxicity in spinal and bulbar muscular atrophy

Expansion of polyglutamine in the gene coding for androgen receptor (AR) is responsible for the degeneration and loss of lower motor neurons in spinal and bulbar muscular atrophy (SBMA). SBMA is one out of nine neurological conditions caused by expanded polyglutamine. Recent evidence suggests the involvement of native protein structure and function in the pathogenesis of polyglutamine diseases. However, the details of how protein context affects disease pathogenesis are poorly understood. We identified protein arginine methyltransferase 6 (PRMT6) as a novel co-activator of normal and mutant androgen receptor, whose function is enhanced by polyglutamine expansion. The interaction of PRMT6 with mutant androgen receptor requires the steroid receptor interaction motif, LXXLL, of PRMT6 and the activating function 2 (AF-2) of androgen receptor. The catalytic activity of PRMT6 is also required. Consistent with this, we show that androgen receptor is a substrate of PRMT6. PRMT6 methylates the androgen receptor at the arginine residues spanning the Akt consensus sites RXRXXS. Importantly, arginine methylation by PRMT6 and serine phosphorylation by Akt at these sites is mutually exclusive. Knock down of PRMT6 in flies attenuates the degenerative phenotype caused by mutant androgen receptor. Collectively, these data provide insights into the mechanism through which protein structure and function cooperate to cause neurodegeneration and implicate arginine methylation and PRMT function in the pathogenesis of polyglutamine diseases.