Mechanisms Mediating Spinal and Bulbar Muscular Atrophy: Investigations into Polyglutamine-Expanded Androgen Receptor Function and Dysfunction

Abstract

Spinal and bulbar muscular atrophy (SBMA, Kennedy’s disease), a late-onset neuromuscular disorder, is caused by expansion of the polymorphic polyglutamine tract in the androgen receptor (AR). The AR is a ligand-activated transcription factor, but plays roles in other cellular pathways. In SBMA, selective motor neuron degeneration occurs in the brainstem and spinal cord, thus the causes of neuronal dysfunction have been studied. However, pathogenic pathways in muscles may also be involved. Cultured cells, fly and mouse models are used to study the molecular mechanisms leading to SBMA. Both the structure of the polyglutamine-expanded AR (polyQ AR) and its interactions with other proteins are altered relative to the normal AR. The ligand-dependent translocation of the polyQ AR to the nucleus appears to be critical, as are interdomain interactions. The polyQ AR, or fragments thereof, can form nuclear inclusions, but their pathogenic or protective nature is unclear. Other data suggests soluble polyQ AR oligomers can be harmful. Post-translational modifications such as phosphorylation, acetylation, and ubiquitination influence AR function and modulate the deleterious effects of the polyQ AR. Transcriptional dysregulation is highly likely to be a factor in SBMA; deregulation of non-genomic AR signaling may also be involved. Studies on polyQ AR-protein degradation suggest inhibition of the ubiquitin proteasome system and changes to autophagic pathways may be relevant. Mitochondrial function and axonal transport may also be affected by the polyQ AR. Androgens, acting through the AR, can be neurotrophic and are important in muscle development; hence both loss of normal AR functions and gain of novel harmful functions by the polyQ AR can contribute to neurodegeneration and muscular atrophy. Thus investigations into polyQ AR function have shown that multiple complex mechanisms lead to the initiation and progression of SBMA.

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

“…In children with autism, elevated mtDNA damage was observed [211]. Neurofibromatosis type 1 (NF1) with somatic mitochondrial mutations [212], Spinal and Bulbar muscular atrophy or Kennedy disease, (a motor neuron disorders) also exhibit mtDNA damage [213]. Somatic mutations in neuronal mtDNA causes ATP depletion, increased oxidative stress, and in turn leading to nuclear genome damage [214].…”

Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients

“…According to the International Prostate Symptom Score (IPSS), 23 lower urinary tract symptoms (LUTS) were classified as mild (IPSS 0-7), moderate (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and severe (>19) (see online supplementary material). Seven patients reporting severe LUTS (IPSS>19) were further characterised by prostate volume analysis by transabdominal ultrasonography 24 and videourodynamic evaluation performed according to the International Continence Society (ICS) recommendations.…”

“…In SBMA, polyQ-AR accumulates in the nucleus, causing cell toxicity which is considered a major pathogenic mechanism. 10 Nuclear inclusions of the mutated protein are a pathological hallmark of polyQ diseases. Diffuse nuclear and cytoplasmic polyQ-AR accumulation is found in residual motor neurons, as well as in several neural and non-neural tissues in SBMA.…”

The Role of the Protein Quality Control System in SBMA

“…Their activity is mainly related to the tight functional relationship that exists between the UPS and autophagy. Indeed, in a Drosophila model of SBMA, HDAC6 overexpression was able to rescue the eye degeneration induced by ARpolyQ as a consequence of a malfunctioning UPS (see (Beitel, et al, 2013) for review). The action of HDAC6 was initially related to its potential to activate a compensatory activation of the autophagic pathway (see also below) in response to UPS impairment (Pandey, et al, 2007), since HDAC6 also controls autophagosome maturation.…”