Kennedy's Disease

Abstract

X-linked spinal and bulbar muscular atrophy is a degenerative disease affecting motor neurons that is caused by polyglutamine (polyQ) expansion within the androgen receptor (AR). The polyQ-expanded form of AR is cytotoxic to cells, and proteolytic cleavage enhances cell death. The intracellular signaling pathways activated and/or required for cell death induced by the expanded form of AR (AR112) are unknown. We found that AR regulates mitogen-activated protein kinase (MAP kinase) pathways and, therefore, hypothesized that these pathway(s) may be required for AR112-induced cell death. The polyQ expansion in AR activates three MAP kinase pathways, causing increasing levels of phosphorylation of p44/42, p38, and SAPK/JNK MAP kinase. Inhibitors of either the JNK or p38 pathways had no effect on AR112-induced cell death, suggesting they are not required for polyQ-induced cell death. Strikingly, the MEK1/2 inhibitor, U0126, which selectively inhibits the p44/42 MAP kinase pathway, reduces AR112-stimulated cell death. The inhibition of the MEK1/2 pathway correlates directly with a change in phosphorylation state of the androgen receptor. Mutation of the MAP kinase consensus phosphorylation site in AR at serine 514 blocked AR-induced cell death and the generation of caspase-3-derived cleavage products. We propose a mechanism by which phosphorylation at serine 514 of AR enhances the ability of caspase-3 to cleave AR and generate cytotoxic polyQ fragments.Spinal and bulbar muscular atrophy (SBMA), 1 or Kennedy's disease, is an X-linked autosomal dominant degenerative disease of the motor neurons, characterized by progressive muscle atrophy and weakness in male patients (1). The disease is caused by a polyglutamine (polyQ) tract expansion within the transcriptional activation domain of androgen receptor (AR) (2). The normal number of CAG repeats is 11-36, whereas the mutant gene has up to 68 repeats. Presumably SBMA is caused by a gain-of-function mutation because severe testicular feminization patients where AR is fully inactivated do not have motor neuron disease (3, 4). However, male patients with SBMA exhibit some symptoms of partial androgen insensitivity, including gynecomastia, small testicles, and feminization, suggesting some impairment of AR function (5). SBMA is one of a growing number of polyQ-repeat diseases, including Huntington's disease and the spinocerebellar ataxias, that are characterized by the death of specific neuronal subsets (6). It is particularly attractive to study the effect of a polyQ expansion in the context of AR because, unlike the other polyQ disease proteins, it has a well characterized function. AR is a transcription factor and a member of a large family of steroid hormone receptors (7,8).Almost all the polyQ proteins identified to date are substrates for cell death proteases or caspases (9 -13). The expanded form of AR is toxic to cells in both cell culture systems and transgenic animal models (9,14). Recent studies both in Drosophila and in transgenic mouse models of SBMA, expressing fu...

Huntingtin Phosphorylation Sites Mapped by Mass Spectrometry

“…Other work on Htt as well as the androgen receptor has shown that phosphorylation at more distal sites can modulate cleavage. In a related polyglutamine disease, Kennedy disease, we have shown that the phosphorylation of androgen receptor modulates proteolysis and toxicity (38). Our studies found that phosphorylation at Ser-514 of the androgen receptor, a site distal to the caspase cleavage site at amino acid 154, enhanced cellular toxicity and the production of cytotoxic fragments.…”

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

“…Alternatively, SUMO modification of the SC motifs in AR may prevent proteolytic steps that are thought to be involved in the generation of toxic polyglutamine-containing fragments (77,78). In this regard, SUMOylation could antagonize the phosphorylationdependent caspase 3 cleavage of AR, which is closely associated with neuronal toxicity (79).…”

Elevated Testosterone Induces Apoptosis in Neuronal Cells

“…For example, testosterone activation of the androgen receptor increases the expression of cytoskeleton proteins, such as tubulin (63) and neuritin (64), which are important for neurite outgrowth and neuronal differentiation. Mutations of the androgen receptor that cause aggregation of polyglutamine-expanded protein induce cytotoxicity with normal levels of testosterone (65,66), a primary cause of Kennedy syndrome (67). The effect of high testosterone concentration on cell function in these altered cells is not known.…”