ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2009
Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 61 citations in OpenAlex.
- Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.Acta neuropathologica communications · 2023Article
- Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy.Cell death & disease · 2022Article
- Review
- Autophagic and Proteasomal Mediated Removal of Mutant Androgen Receptor in Muscle Models of Spinal and Bulbar Muscular Atrophy.Frontiers in endocrinology · 2019Article
- Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients.Acta neuropathologica · 2018Article
- PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis.Science translational medicine · 2017Article
- Modulation of Molecular Chaperones in Huntington's Disease and Other Polyglutamine Disorders.Molecular neurobiology · 2017Review
- Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Article
- PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically.Nature medicine · 2016Article
- Trinucleotide repeats and protein folding and disease: the perspective from studies with the androgen receptor.Future science OA · 2015Review
- Proteolytic cleavage of ataxin-7 promotes SCA7 retinal degeneration and neurological dysfunction.Human molecular genetics · 2015Article
- Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis.The Journal of biological chemistry · 2015Article
- Mitochondrial dysfunction in Kennedy's disease: a new pharmacological target?Annals of translational medicine · 2015Article
- The role of the immune system in triplet repeat expansion diseases.Mediators of inflammation · 2015Review
- Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA.Nature neuroscience · 2014Article
- Androgen receptor (AR) positive vs negative roles in prostate cancer cell deaths including apoptosis, anoikis, entosis, necrosis and autophagic cell death.Cancer treatment reviews · 2014Review
- Gene expression profiling associated with angiotensin II type 2 receptor-induced apoptosis in human prostate cancer cells.PloS one · 2014Article
- Pathogenic mechanisms and therapeutic strategies in spinobulbar muscular atrophy.CNS & neurological disorders drug targets · 2013Review
- Clearance of the mutant androgen receptor in motoneuronal models of spinal and bulbar muscular atrophy.Neurobiology of aging · 2013Article
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Authors and funding
13 authors at 6 institutions in 1 country.
Funding
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.
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