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

2015; Cell Press; Volume: 85; Issue: 1 Linguagem: Inglês

10.1016/j.neuron.2014.12.031

1097-4199

Chiara Scaramuzzino, Ian Casci, Sara Parodi, Patricia Lievens, María José Polanco, Carmelo Milioto, Mathilde Chivet, John Monaghan, Ashutosh Mishra, Nisha M. Badders, Tanya Aggarwal, Christopher Grunseich, Fabio Sambataro, Manuela Basso, Frank O. Fackelmayer, J. Paul Taylor, Udai Bhan Pandey, Maria Pennuto,

Neurogenetic and Muscular Disorders Research

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.