Native Functions of the Androgen Receptor Are Essential to Pathogenesis in a Drosophila Model of Spinobulbar Muscular Atrophy

Abstract

Summary Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by expansion of a polyglutamine tract in the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. Mutant AR toxicity requires binding of its hormone ligand, suggesting that pathogenesis involves ligand-induced changes in AR. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated events downstream of ligand-dependent AR activation in a Drosophila model of SBMA. We show that nuclear translocation of AR is necessary but not sufficient for toxicity and that DNA binding by AR is necessary for toxicity. Mutagenesis studies demonstrated that a functional AF-2 domain is essential for toxicity, a finding corroborated by a genetic screen that identified AF-2 interactors as dominant modifiers of degeneration. These findings indicate that SBMA pathogenesis is mediated by misappropriation of native protein function, a mechanism that may apply broadly to polyglutamine diseases.

Proteasome-mediated Proteolysis of the Polyglutamine-expanded Androgen Receptor Is a Late Event in Spinal and Bulbar Muscular Atrophy (SBMA) Pathogenesis

“…While signs of androgen insensitivity are sometimes seen in SBMA, the disease is not due to a loss of AR function but rather to a gain of a toxic property of the mutant polyglutamine-expanded androgen receptor. Although the precise mechanistic pathway leading to AR misfolding, aggregation, and its subsequent toxicity has not been fully elucidated, it is known that binding of one of the natural AR ligands, testosterone or 5␣-dihydrotestosterone, and nuclear localization are required for both motor dysfunction and neuropathology (9,11,12).…”

Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6

“…The pathogenesis of polyQ diseases is complex, but it has been suggested that the expanded polyQ protein causes disease through a toxic gain-of-function mechanism. More recently, protein context and normal protein activity have been shown to be critical in the pathogenesis of these diseases (4,5). In SCA6, the CAG repeat encodes a polyQ tract in the cytoplasmic tail domain of the Ca v 2.1 channel, a pore-forming subunit of the P/Q type voltage-gated calcium channels (6).…”

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

“…Large-scale and candidate-based genetic-modifier screens have been extremely successful in revealing pathways novel to polyQ disease protein toxicity (Fernandez-Funez et al 2000;Kazemi-Esfarjani and Benzer 2000;Bilen and Bonini 2007;Nedelsky et al 2010). Examples include a large-scale EP screen for polyQ modifiers that revealed new roles for microRNAs (miRNAs) in maintaining the integrity of the nervous system (Bilen et al 2006;Liu et al 2012).…”