Kennedy's disease: pathogenesis and clinical approaches

Abstract

Kennedy's disease, also known as spinal and bulbar muscular atrophy, is a progressive degenerative condition affecting lower motor neurons. It is one of nine neurodegenerative disorders caused by a polyglutamine repeat expansion. Affecting only men, Kennedy's disease is the only one of these conditions that follows an X-linked mode of inheritance. The causative protein in Kennedy's disease, with a polyglutamine expansion residing in the first N-terminal domain, is the androgen receptor. Research in this field has made significant advances in recent years, and with the increased understanding of pathogenic mechanisms, feasible approaches to treatments are being investigated. In Kennedy's disease research, the most significant issue to emerge recently is the role of androgens in exacerbating the disease process. On the basis of animal experiments, a viable hypothesis is that higher circulating levels of androgens in men could trigger the degeneration of motor neurons causing this disease, and that lower levels in heterozygous and homozygous women are protective. This is a major issue, as treatment of individuals affected by Kennedy's disease with testosterone has been considered a reasonable therapy by some neurologists. The rationale behind this approach relates to the fact that Kennedy's disease is accompanied by mild androgen insensitivity. It was therefore believed that treatment with high doses of testosterone might compensate for this loss of androgen action, with the added benefit of preventing muscle wasting. The current review provides an overview of recent advances in the field of Kennedy's disease research, including approaches to treatment.

Testosterone metabolism: a possible biological underpinning of non-verbal IQ in intellectually gifted girls

“…Its effect on tissues, brain being no exception, can be mediated via the androgen receptor (AR) in a classical genomic pathway. An androgen receptor is a nuclear transcription factor whose N-terminal transactivation domain is encoded by a variable sequence of CAG triplets with a normal range from 11 to 30 repeats in humans (Greenland and Zajac 2004). Within this range, higher number of CAG repeats (indicating lower transactivational activity of AR) positively correlates with increased speed of neural transmission (measured in simple reaction experiments).…”

Epigenetic modifications in trinucleotide repeat diseases

“…Testosterone-dependent nuclear translocation and accumulation of toxic poly-Q AR is thought to trigger degeneration of motor neurons [138]. Carrier and homozygous females are asymptomatic due to reduced levels of testosterone [139,140]. Poly-Q proteins can cause transcriptional dysregulation and mutant AR inhibits histone acetyltransferase proteins [141].…”

The roles of proteolysis and nuclear localisation in the toxicity of the polyglutamine diseases. A review

“…SBMA does however result in minor features of androgen insensitivity, such as gynaecomastia and reduced fertility (Greenland and Zajac, 2004).…”

“…While it might seem logical to treat SBMA with exogenous androgens, several studies in vitro and in transgenic models have now reported that such treatment exacerbates neurotoxicity (Katsuno et al, 2002;Walcott and Merry, 2002). While the mechanism of this exacerbation is uncertain, it most likely relates to increased nuclear translation of the ligand-AR complex (Walcott and Merry, 2002;Greenland and Zajac, 2004).…”