Androgen receptor and Kennedy disease/spinal bulbar muscular atrophy

Abstract

Kennedy Disease/Spinal Bulbar Muscular Atrophy (KD/SBMA) is a progressive neurodegenerative disease caused by genetic polyglutamine expansion of the androgen receptor. We have recently found that overexpression of wildtype androgen receptor in skeletal muscle of transgenic mice results in a KD/SBMA phenotype. This surprising result challenges the orthodox view that KD/SBMA requires expression of polyglutamine expanded androgen receptor within motoneurons. Theories relating to the etiology of this disease drawn from studies of human patients, cellular and mouse models are considered with a special emphasis on potential myogenic contributions to as well as the molecular etiology of KD/SBMA. KeywordsNeuromuscular systems; Sexual dimorphism; Testosterone; Axonopathy; Myopathy; Polyglutamine disease Role of androgen receptor in neuromuscular systemsAndrogens are generally considered to have anabolic actions on neuromuscular systems. Sexually dimorphic neuromuscular systems provide excellent models for understanding how androgens exert these anabolic actions, and studies of these model systems have generally concluded that androgenic anabolic actions are largely, although not exclusively, mediated via androgen receptors (AR). Several reviews on this topic exist, including an article in this issue (Forger and Sengelaub), and so we will only briefly comment on these studies in order to introduce our experiments relating to androgens and neuromuscular pathology.The importance of AR to sexual differentiation of rodent copulatory neuromuscular systems is illustrated by testicular feminization mutation (Tfm) mutant rats, in which the normal function of androgen in promoting greater levator ani (LA) muscle size and spinal nucleus of the bulbocavernosus (SNB) motoneuron number and size is disabled by a loss of function mutation in the ligand binding domain of the AR gene (Breedlove and Arnold, 1981;Forger

Subcellular effects of myocyte-specific androgen receptor overexpression in mice

“…motor impairment and wasting) has proven difficult (Monks et al 2007). As we have argued elsewhere (Monks et al 2008), this difficulty might be explained by a quantitative difference resulting in a threshold for pathology being met. We might, therefore, predict that testosterone-exposed L78 and L141 mice would exhibit similar alterations in cellular processes, but that they would be more pronounced in L141 mice, culminating in systemic dysfunction.…”

Perspectives of Kennedy's disease

“…As an example, the view that BSMA requires poly-G-expanded AR for disease expression has been recently challenged by the finding that over-expression of wild-type AG in the skeletal muscle of transgenic mice may also manifest as BSMA [88]. Also poly-Q-expanded AR acting in muscle fibers can trigger a BSMA phenotype and secondarily may cause motor neuron dysfunction, challenging the role of AR in muscle [2].…”

The N-terminal domain of the androgen receptor drives its nuclear localization in castration-resistant prostate cancer cells

“…Many studies have revealed various types of AR gene mutations that contribute to diseases including spinobulbar muscular atrophy (SBMA) (26), androgen insensitivity syndrome (AIS) (27), and prostate cancer (28, 29). Several reports have revealed that mutant ARs obtained from both AIS and prostate cancer patients may exhibit abnormal intracellular localization and lower capacity for ligand-dependent translocation when compared with wild-type AR.…”