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Sci Transl Med. 2016 Dec 21;8(370):370ra181. doi: 10.1126/scitranslmed.aaf9526.

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

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Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Departments of Cellular and Molecular Medicine, Pediatrics, and Neurosciences, and Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biology and Genetics, University of Verona, 37134 Verona, Italy.
Laboratory for Applications of Synchrotron Radiation, Karlsruhe Institute of Technology, and abcr GmbH, Karlsruhe, Germany.
Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia.
Skolkovo Institute of Science and Technology, Skolkovo, 143025 Moscow, Russia.
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Experimental and Clinical Medical Sciences (DISM), University of Udine, 33100 Udine, Italy.
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv 69978, Israel.
Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.


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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