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.

Abstract

Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. SBMA belongs to the family of polyQ diseases, which are fatal neurodegenerative disorders mainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of misfolded proteins in the form of aggregates. The neurotoxicity of the polyQ proteins can be modified by phosphorylation at specific sites, thereby providing the rationale for the development of disease-specific treatments. We sought to identify signaling pathways that modulate polyQ-AR phosphorylation for therapy development. We report that cyclin-dependent kinase 2 (CDK2) phosphorylates polyQ-AR specifically at Ser96. Phosphorylation of polyQ-AR by CDK2 increased protein stabilization and toxicity and is negatively regulated by the adenylyl cyclase (AC)/protein kinase A (PKA) signaling pathway. To translate these findings into therapy, we developed an analog of pituitary adenylyl cyclase activating polypeptide (PACAP), a potent activator of the AC/PKA pathway. Chronic intranasal administration of the PACAP analog to knock-in SBMA mice reduced Ser96 phosphorylation, promoted polyQ-AR degradation, and ameliorated disease outcome. These results provide proof of principle that noninvasive therapy based on the use of PACAP analogs is a therapeutic option for SBMA.

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