Human Molecular Genetics Advance Access originally published online on June 13, 2006
Human Molecular Genetics 2006 15(14):2225-2238; doi:10.1093/hmg/ddl148
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Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy
1 Department of Laboratory Medicine, 2 Department of Medicine, 3 Department of Neurology, 4 Center for Neurogenetics and Neurotherapeutics, University of Washington Medical Center, Seattle, WA, USA and 5 Department of Biology, Hope College, Holland, MI, USA
* To whom correspondence should be addressed at: Department of Laboratory Medicine, University of Washington Medical Center, PO Box 357110, Room NW 120, Seattle, WA 98195-7110, USA. Tel: +1 2065982138; Fax: +1 2065986189; Email: laspada{at}u.washington.edu
Received April 9, 2006; Accepted June 2, 2006
X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a polyglutamine (polyQ) disease in which the affected males suffer progressive motor neuron degeneration accompanied by signs of androgen insensitivity, such as gynecomastia and reduced fertility. SBMA is caused by CAG repeat expansions in the androgen receptor (AR) gene resulting in the production of AR protein with an extended glutamine tract. SBMA is one of nine polyQ diseases in which polyQ expansion is believed to impart a toxic gain-of-function effect upon the mutant protein, and initiate a cascade of events that culminate in neurodegeneration. However, whether loss of a disease protein's normal function concomitantly contributes to the neurodegeneration remains unanswered. To address this, we examined the role of normal AR function in SBMA by crossing a highly representative AR YAC transgenic mouse model with 100 glutamines (AR100) and a corresponding control (AR20) onto an AR null (testicular feminization; Tfm) background. Absence of endogenous AR protein in AR100Tfm mice had profound effects upon neuromuscular and endocrine-reproductive features of this SBMA mouse model, as AR100Tfm mice displayed accelerated neurodegeneration and severe androgen insensitivity in comparison to AR100 littermates. Reduction in size and number of androgen-sensitive motor neurons in the spinal cord of AR100Tfm mice underscored the importance of AR action for neuronal health and survival. Promoter–reporter assays confirmed that AR transactivation competence diminishes in a polyQ length-dependent fashion. Our studies indicate that SBMA disease pathogenesis, both in the nervous system and the periphery, involves two simultaneous pathways: gain-of-function misfolded protein toxicity and loss of normal protein function.