title: Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy.
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 Ser96Phosphorylation 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 Ser96phosphorylation, 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.
authors.affiliation: 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.
authors.forename: Maria Josè
authors.initials: MJ
authors.lastname: Polanco
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Parodi
authors.affiliation: Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Piol
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Conor
authors.initials: C
authors.lastname: Stack
authors.affiliation: Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Chivet
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Contestabile
authors.affiliation: 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.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Miranda
authors.affiliation: Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biology and Genetics, University of Verona, 37134 Verona, Italy.
authors.forename: Patricia M-J
authors.initials: PM
authors.lastname: Lievens
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Espinoza
authors.affiliation: Laboratory for Applications of Synchrotron Radiation, Karlsruhe Institute of Technology, and abcr GmbH, Karlsruhe, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Jochum
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rocchi
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Grunseich
authors.affiliation: Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia.|Skolkovo Institute of Science and Technology, Skolkovo, 143025 Moscow, Russia.
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
authors.forename: Andrew C B
authors.initials: AC
authors.lastname: Cato
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.affiliation: 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.
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
authors.affiliation: Department of Experimental and Clinical Medical Sciences (DISM), University of Udine, 33100 Udine, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sambataro
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.affiliation: 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.
authors.forename: Illana
authors.initials: I
authors.lastname: Gozes
authors.affiliation: Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy. mpennuto@dti.telethon.it.|Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pennuto
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D020966:Muscular Disorders, Atrophic / Q000378:metabolism*; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry*; D010766:Phosphorylation; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D011489:Protein Denaturation; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D010455:Peptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011944:Receptors, Androgen; D005973:Glutamine; C097188:polyglutamine; D017868:Cyclic AMP-Dependent Protein Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2