Research ArticleNeurodegenerative Disease

Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy

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Science Translational Medicine  21 Dec 2016:
Vol. 8, Issue 370, pp. 370ra181
DOI: 10.1126/scitranslmed.aaf9526

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Purging X-tra protein aggregates

An indirect attack on the causative aberrant protein might treat a fatal X-linked neurodegenerative disease. Spinal bulbar muscular atrophy (SBMA) is a fatal neuromuscular disorder caused by a genetic defect that gives rise to polyglutamine (polyQ) expansion in the androgen receptor protein (polyQ-AR). The run of glutamine residues produces a toxic misfolded protein that aggregates in cells. The toxic effects can be mitigated by the protein’s phosphorylation status. Polanco et al. took advantage of this property to attack the disease at its molecular origin.

In pinpointing the cell signaling pathways that modulate polyQ-AR phosphorylation, the authors found that the cell cycle regulatory protein cyclin-dependent kinase 2 (CDK2) phosphorylated polyQ-AR at Ser96 and that this phosphorylation event increased and stabilized the protein, and enhanced its toxicity. A second cellular function—the adenylyl cyclase (AC)/protein kinase A (PKA) signaling pathway—negatively regulated Ser96 phosphorylation, which blunted protein stability and, in turn, its toxicity. The authors then translated these findings by engineering an analog of pituitary adenylyl cyclase activating polypeptide (PACAP), which activates the AC/PKA pathway. When SBMA mice were given the analog intranasally, they displayed reduced Ser96 phosphorylation, enhanced polyQ-AR degradation, and—most exciting of all—an obliteration of disease outcomes.

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