title: Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.
abstract: Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.
authors.affiliation: Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Monyak
authors.affiliation: Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Emerson
authors.affiliation: Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.|Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Schoenfeld
authors.affiliation: Department of Neuroscience and Howard Hughes Medical Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Pediatric Neurology, Center for Neuroscience, University of Alberta, Edmonton, AB, Canada.
authors.forename: D B
authors.initials: DB
authors.lastname: Chambers
authors.affiliation: Department of Pediatric Neurology, Center for Neuroscience, University of Alberta, Edmonton, AB, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Rosenfelt
authors.affiliation: Department of Pediatric Neurology, Center for Neuroscience, University of Alberta, Edmonton, AB, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Langer
authors.affiliation: Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Hinchey
authors.affiliation: Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.|Department of Dermatology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Choi
authors.affiliation: Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: T V
authors.initials: TV
authors.lastname: McDonald
authors.affiliation: Department of Pediatric Neurology, Center for Neuroscience, University of Alberta, Edmonton, AB, Canada.
authors.forename: F V
authors.initials: FV
authors.lastname: Bolduc
authors.affiliation: Department of Neuroscience and Howard Hughes Medical Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sehgal
authors.affiliation: Departments of Psychiatry and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: S M J
authors.initials: SMJ
authors.lastname: McBride
authors.affiliation: Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Jongens
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000235:genetics; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008568:Memory / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D007328:Insulin; C467328:FMR1 protein, Drosophila