Spinobulbar muscular atrophy (SBMA) is an inherited X-linked neurodegenerative disease caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract (polyQ) in the N-terminal region of the androgen receptor (AR). The mutant protein forms intranuclear aggregates in motor neurons of the spinal cord and brainstem and causes the death of those specific motor neurons. The AR is a nuclear hormone receptor and it functions as a transcription factor after binding its specific ligands (testosterone or dihidrotestosterone, DHT) in the C-terminal ligand-binding domain (LBD). AR binding by hormone is crucial for the pathology in SBMA. Several post-translational events occur upon hormone binding by the AR, including the interaction between the AF2 domain (within the LBD) and the FXXLF motif in the N-terminal domain (N/C interaction), and the phosphorylation of the AR at specific serine residues (Ser). Recent studies from our laboratory showed that the N/C interaction is required for both AR aggregation and cell death, and that the N/C interaction is associated with phosphorylation at Ser81 and Ser308. Mutations in the FXXLF motif or treatment with bicalutamide, an AR antagonist, prevented the N/C interaction in our PC12 cell model of SBMA (expressing 112Q repeat-containing AR in an inducible manner), and decreased aggregation, cell death and phosphorylation at Ser81 and Ser308, suggesting a relationship between the N/C interaction, phosphorylation and SBMA pathology. In this study we tested several selective AR modulators (SARMs) known to prevent the N/C interaction for their effects on polyglutamine-dependent AR aggregation and cell death. Consistent with our hypothesis that the N/C interaction is critical for mutant AR aggregation, the treatment of our SBMA cells with six SARMs decreased mutant AR toxicity and prevented AR aggregation, while also decreasing the phosphorylation at Ser81 and Ser308. Although the effect of the SARMs depended on the dose and specific compound, these molecules all represent potential therapeutic candidates for SBMA.
|Titolo:||Effects of selective androgen receptor modulators in experimental models of SBMA|
BOLZONI, ELENA (Primo)
|Data di pubblicazione:||2009|
|Parole Chiave:||SARM ; SBMA ; polyglutamine ; androgen receptor|
|Citazione:||Effects of selective androgen receptor modulators in experimental models of SBMA / E. Bolzoni, C.R. Orr, Y. Liu, D. McDonnell, E. Wilson, D.E. Merry. ((Intervento presentato al 4. convegno Meeting on the Molecular Mechanisms of Neurodegeneration tenutosi a Milano nel 2009.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|