The effect of polyglutamine expansion in the human androgen receptor on its ability to suppress β-catenin-Tcf/Lef dependent transcription

• Published in: Neuroscience letters Vol. 354; no. 1; pp. 54 - 58
• Main Authors: Cullen, D.A., Killick, R., Leigh, P.N., Gallo, J.-M.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 02.01.2004; Elsevier
• Subjects: Androgen receptor; beta Catenin; Biological and medical sciences; Cell Line; Cytoskeletal Proteins - metabolism; Diseases of striated muscles. Neuromuscular diseases; DNA Repeat Expansion; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Genes, Reporter; Humans; Kennedy's disease; Kidney - cytology; Lymphoid Enhancer-Binding Factor 1; Medical sciences; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - physiopathology; Nerve Degeneration - genetics; Nerve Degeneration - physiopathology; Neurodegeneration; Neurology; Peptides - genetics; Polyglutamine expansion; Proto-Oncogene Proteins - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction - physiology; Trans-Activators - metabolism; Transcription Factors - metabolism; Transcription, Genetic - physiology; Vertebrates: nervous system and sense organs; Wnt; Wnt Proteins; Zebrafish Proteins; β-Catenin; Polyglutamine expansion; β-Catenin; Wnt; Neurodegeneration; Androgen receptor; Kennedy's disease; Human; Neuromuscular diseases; Nervous system diseases; Degeneration; Catenin; Genetic disease
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2003.09.074

Expansion of the polyglutamine repeat region of the androgen receptor (AR) results in Kennedy's disease, a neurological disorder typified by degeneration of motor neurons in the brain stem and spinal cord. As the AR has been shown to inhibit β-catenin dependent (Wnt) signalling we asked if expansion of the polyglutamine repeats might affect this property of the protein. Using the TOPflash/FOPflash reporter assay we found that a pathogenic form of the AR containing 51 glutamine repeats showed a consistent, though minimal, reduction in its ability to inhibit β-catenin-mediated transcription, in comparison to a non-pathogenic form with 20 repeats. A reduced ability to inhibit Wnt signalling may thus contribute in part to the underlying aetiology of Kennedy's disease.