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- W2079172704 endingPage "1997" @default.
- W2079172704 startingPage "1987" @default.
- W2079172704 abstract "Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by a polyglutamine (polyQ) repeat expansion in the androgen receptor (AR). PolyQ-AR neurotoxicity may involve generation of an N-terminal truncation fragment, as such peptides occur in SBMA patients and mouse models. To elucidate the basis of SBMA, we expressed N-terminal truncated AR in motor neuron-derived cells and primary cortical neurons. Accumulation of polyQ-AR truncation fragments in the cytosol resulted in neurodegeneration and apoptotic, caspase-dependent cell death. Using primary neurons from mice transgenic or deficient for apoptosis-related genes, we determined that polyQ-AR apoptotic activation is fully dependent on Bax. Jun N-terminal kinase (JNK) was required for apoptotic pathway activation through phosphorylation of c-Jun. Expression of polyQ-AR in DP5/Hrk null neurons yielded significant protection against apoptotic activation, but absence of Bim did not provide protection, apparently due to compensatory upregulation of DP5/Hrk or other BH3-only proteins. Misfolded AR protein in the cytosol thus initiates a cascade of events beginning with JNK and culminating in Bax-dependent, intrinsic pathway activation, mediated in part by DP5/Hrk. As apoptotic mediators are candidates for toxic fragment generation and other cellular processes linked to neuron dysfunction, delineation of the apoptotic activation pathway induced by polyQ-expanded AR may shed light on the pathogenic cascade in SBMA and other motor neuron diseases." @default.
- W2079172704 created "2016-06-24" @default.
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- W2079172704 date "2009-02-18" @default.
- W2079172704 modified "2023-10-16" @default.
- W2079172704 title "Polyglutamine-Expanded Androgen Receptor Truncation Fragments Activate a Bax-Dependent Apoptotic Cascade Mediated by DP5/Hrk" @default.
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