TY - JOUR

T1 - Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy

AU - Polanco, Maria Josè

AU - Parodi, Sara

AU - Piol, Diana

AU - Stack, Conor

AU - Chivet, Mathilde

AU - Contestabile, Andrea

AU - Miranda, Helen C.

AU - Lievens, Patricia M.J.

AU - Espinoza, Stefano

AU - Jochum, Tobias

AU - Rocchi, Anna

AU - Grunseich, Christopher

AU - Gainetdinov, Raul R.

AU - Cato, Andrew C.B.

AU - Lieberman, Andrew P.

AU - La Spada, Albert R.

AU - Sambataro, Fabio

AU - Fischbeck, Kenneth H.

AU - Gozes, Illana

AU - Pennuto, Maria

PY - 2016/12/21

Y1 - 2016/12/21

N2 - Spinobulbarmuscular 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 disordersmainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of misfolded proteins in the formof aggregates. The neurotoxicity of the polyQproteins can bemodified by phosphorylation at specific sites, thereby providing the rationale for the development of disease-specific treatments.We sought to identify signaling pathways thatmodulate polyQ-AR phosphorylation for therapy development.Wereport 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.

AB - Spinobulbarmuscular 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 disordersmainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of misfolded proteins in the formof aggregates. The neurotoxicity of the polyQproteins can bemodified by phosphorylation at specific sites, thereby providing the rationale for the development of disease-specific treatments.We sought to identify signaling pathways thatmodulate polyQ-AR phosphorylation for therapy development.Wereport 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.

UR - http://www.scopus.com/inward/record.url?scp=85007018158&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aaf9526

DO - 10.1126/scitranslmed.aaf9526

M3 - Article

C2 - 28003546

AN - SCOPUS:85007018158

VL - 8

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 370

M1 - 370ra181

ER -