Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy.
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| 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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| Authors | Maria Josè Polanco, Sara Parodi, Diana Piol, Conor Stack, Mathilde Chivet, Andrea Contestabile, Helen C Miranda, Patricia M-J Lievens, Stefano Espinoza, Tobias Jochum, Anna Rocchi, Christopher Grunseich, Raul R Gainetdinov, Andrew C B Cato, Andrew P Lieberman, Albert R La Spada, Fabio Sambataro, Kenneth H Fischbeck, Illana Gozes, Maria Pennuto |
| Journal | Science translational medicine (Sci Transl Med) Vol. 8 Issue 370 Pg. 370ra181 (12 21 2016) ISSN: 1946-6242 [Electronic] United States |
| PMID | 28003546 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2016, American Association for the Advancement of Science. |
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