Progress in Spinobulbar muscular atrophy research: insights into neuronal dysfunction caused by the polyglutamine-expanded androgen receptor.
Spinobulbar muscular atrophy (SBMA, Kennedy's disease) results from the dysfunction and degeneration of specific motor and sensory neurons. The underlying cause of this ligand-dependent neurodegenerative disease is expansion of the CAG trinucleotide repeat in the androgen receptor (AR) gene which leads to lengthening of the polyglutamine tract in the AR protein. Recently, the effects of the polyglutamine-expanded AR have been explored in a number of cellular and animal models. Common themes include research on polyglutamine-containing nuclear inclusions and the effect of molecular chaperone overexpression on their formation. In addition, investigations have highlighted the role that abnormal transcriptional regulation, proteasome dysfunction and altered axonal transport may play in disease pathogenesis. These studies suggest a number of potential treatments for restoring neuronal function. One of the most interesting advances in SBMA research has been the creation of mouse models that recapitulate the key features of SBMA progression in men. Lowering testosterone levels in affected transgenic male mice rescued, and even reversed the polyglutamine-induced neuromuscular phenotype, indicating that manipulating androgen levels in men could be of therapeutic benefit. Although the question of why only a distinct subset of neurons is affected by polyglutamine expansion of the AR remains unsolved, future research will provide further insights into the mechanisms contributing to disease progression in SBMA.
Beitel
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LK
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, QC, H3T 1E2, Canada. lenore.beitel@mcgill.ca
Scanlon
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Gottlieb
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Trifiro
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D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D006728:Hormones; D006801:Humans; D018832:Molecular Chaperones / Q000502:physiology; D020966:Muscular Disorders, Atrophic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics*; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion / Q000502:physiology*
D006728:Hormones; D018832:Molecular Chaperones; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex