title: Protein arginine methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy.
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.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Scaramuzzino
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Casci
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Neurogenetics Branch, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Parodi
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Department of Life and Reproduction Sciences, Section of Biology and Genetics, University of Verona, 37134 Verona, Italy.
authors.forename: Patricia M J
authors.initials: PMJ
authors.lastname: Lievens
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Dulbecco Telethon Institute Lab of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Polanco
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Dulbecco Telethon Institute Lab of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Milioto
authors.affiliation: Dulbecco Telethon Institute Lab of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Chivet
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
authors.forename: John
authors.initials: J
authors.lastname: Monaghan
authors.affiliation: St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Badders
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Tanya
authors.initials: T
authors.lastname: Aggarwal
authors.affiliation: Neurogenetics Branch, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Grunseich
authors.affiliation: Brain Center for Motor and Social Cognition, Istituto Italiano di Tecnologia@UniPR, 43100 Parma, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sambataro
authors.affiliation: Laboratory of Transcriptional Neurobiology, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Basso
authors.affiliation: Laboratory of Epigenetics and Chromosome Biology, Department of Biomedical Research, Institute for Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, 45110 Ioannina, Greece.
authors.forename: Frank O
authors.initials: FO
authors.lastname: Fackelmayer
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
authors.forename: Udai Bhan
authors.initials: UB
authors.lastname: Pandey
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Dulbecco Telethon Institute Lab of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy. Electronic address: maria.pennuto@unitn.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Pennuto
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D020966:Muscular Disorders, Atrophic / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics*; D010766:Phosphorylation; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012333:RNA, Messenger; D011944:Receptors, Androgen; C097188:polyglutamine; C447833:PRMT6 protein, human; C577312:PRMT6 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D051057:Proto-Oncogene Proteins c-akt