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

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2015 Jan 9

PMID 25569348

Citations 56

Authors

Chiara Scaramuzzino

Ian Casci

Sara Parodi

Patricia M J Lievens

Maria J Polanco

Carmelo Milioto

Mathilde Chivet

John Monaghan

Ashutosh Mishra

Nisha Badders

Tanya Aggarwal

Christopher Grunseich

Fabio Sambataro

Manuela Basso

Frank O Fackelmayer

J Paul Taylor

Udai Bhan Pandey

Maria Pennuto

Affiliations

Soon will be listed here.

Abstract

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.

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