The long-term goal is to understand the molecular basis of spinobulbar muscular atrophy (SBMA) so that treatment may be developed. SBMA is a hereditary disease characterized by progressive loss of motor neurons in the brainstem and spinal cord. SBMA is caused by trinucleotide (CAG) repeat expansion in the androgen receptor (AR) gene leading to polyglutamine expansion in AR protein. Eight other diseases have the same kind of mutation: Huntington's disease, DRPLA, and six forms of spinocerebellar ataxia. Expanded polyglutamine itself is toxic. However, despite widespread and overlapping expression of the disease proteins, these disorders are distinguished by selective vulnerability of different populations of neurons. This observation indicates that expanded polyglutamine cannot be the sole determinant of neurodegeneration.
The first aim of this proposal will address the role of discrete AR functional domains in the initiation and pathogenesis of SBMA. Another important determinant in the initiation and progression of polyglutamine disease is that status of the cellular mechanisms responsible for protecting cells from toxic proteins. Two pathways of protein degradation, the ubiquitin-proteasome system (UPS) and autophagy, have been implicated as playing important roles in polyglutamine diseases. The UPS is a multi-component system that coordinates timely and specific degradation of intracellular protein. Autophagy is a lysosome-mediated catabolic pathway and is the primary means of bulk degradation of cytoplasmic components. In the second two aims of this proposal, we will test specific hypotheses relating to the role of the UPS and autophagy in the pathogenesis of SBMA.
Aim 1 : Defining the contributions of specific AR domains to polyglutamine-expanded AR toxicity.
Aim 2 : To test the hypothesis that SBMA pathogenesis is associated with impaired UPS function in vivo.
Aim 3 : To determine the role of autophagy in SBMA pathogenesis using histological and genetic approaches

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurodegeneration and Biology of Glia Study Section (NDBG)
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Gubitz, Amelie
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St. Jude Children's Research Hospital
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Bott, Laura C; Badders, Nisha M; Chen, Ke-Lian et al. (2016) A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy. Hum Mol Genet 25:1979-1989
Alami, Nael H; Smith, Rebecca B; Carrasco, Monica A et al. (2014) Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81:536-543
Ramaswami, Mani; Taylor, J Paul; Parker, Roy (2013) Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154:727-36
Kim, Hong Joo; Kim, Nam Chul; Wang, Yong-Dong et al. (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467-73
Lim, Kah-Leong; Ng, Xiao-Hui; Grace, Lim Gui-Yin et al. (2012) Mitochondrial dynamics and Parkinson's disease: focus on parkin. Antioxid Redox Signal 16:935-49
Todd, Peter K; Oh, Seok Yoon; Krans, Amy et al. (2010) Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome. PLoS Genet 6:e1001240
Lee, Joo-Yong; Koga, Hiroshi; Kawaguchi, Yoshiharu et al. (2010) HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 29:969-80
La Spada, Albert R; Taylor, J Paul (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11:247-58
Gao, Ya-sheng; Hubbert, Charlotte C; Yao, Tso-Pang (2010) The microtubule-associated histone deacetylase 6 (HDAC6) regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation. J Biol Chem 285:11219-26
Nedelsky, Natalia B; Pennuto, Maria; Smith, Rebecca B et al. (2010) Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy. Neuron 67:936-52

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