Specific N-terminal mutations in the human androgen receptor induce cytotoxicity.
Polyglutamine (polyQ) stretch amplification in different proteins causes neurodegenerative disease. These proteins form intracellular aggregates thought to be cytotoxic but differ in pathology and tissue specificity. Here, we demonstrate that specific sequences outside the polyQ stretch of the human androgen receptor contribute to polyQ pathology. An exchange of two N-terminal serine phosphorylation residues to alanine in the wild type androgen receptor (ARQ22dm) resulted in cytoplasmic accumulation and increased early hormone-dependent aggregation of the receptor. In a Drosophila model, the ARQ22dm was cytotoxic, and developing larvae expressing this receptor showed behavioral abnormalities and severely impaired locomotion. In contrast, the same double mutation in an androgen receptor with an extended polyQ stretch was less toxic. The response of the receptors to inhibitors of polyglutamine toxicity is altered by the amino acid exchanges suggesting that careful consideration is needed in the choice of potential therapies of disorders involving toxic polyQ species.
Funderburk
Sarah F
SF
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, PO Box 3640, D-76021 Karlsruhe, Germany.
Shatkina
Liubov
L
Mink
Sigrun
S
Weis
Qun
Q
Weg-Remers
Susanne
S
Cato
Andrew C B
AC
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001526:Behavioral Symptoms / Q000235:genetics / Q000473:pathology; D002087:Butyrates / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D006801:Humans; D007814:Larva; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008550:Melatonin / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics*; D012694:Serine / Q000235:genetics; D016019:Survival Analysis; D014162:Transfection / Q000379:methods; D018911:Trinucleotide Repeats / Q000235:genetics*
D002087:Butyrates; D029721:Drosophila Proteins; D010446:Peptide Fragments; D011944:Receptors, Androgen; D012694:Serine; D020929:Mitogen-Activated Protein Kinase Kinases; D008550:Melatonin