title: Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486.
abstract: Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO mouse displays phenotypes similar to symptoms in the human condition--including hyperactivity, repetitive behaviors, and seizures--as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor--which we call FRAX486--also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. bdolan@alum.mit.edu
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Dolan
authors.forename: Sergio G
authors.initials: SG
authors.lastname: Duron
authors.forename: David A
authors.initials: DA
authors.lastname: Campbell
authors.forename: Benedikt
authors.initials: B
authors.lastname: Vollrath
authors.forename: B S
authors.initials: BS
authors.lastname: Shankaranarayana Rao
authors.forename: Hui-Yeon
authors.initials: HY
authors.lastname: Ko
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Lin
authors.forename: Arvind
authors.initials: A
authors.lastname: Govindarajan
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Susumu
authors.initials: S
authors.lastname: Tonegawa
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods; D020195:Epilepsy, Reflex / Q000188:drug therapy / Q000209:etiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D045442:Rotarod Performance Test; D013329:Structure-Activity Relationship; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D054462:p21-Activated Kinases; C581573:6-(2,4-dichlorophenyl)-8-ethyl-2-(3-fluoro-4-(piperazin-1-yl)phenylamino)pyrido(2,3-d)pyrimidin-7(8H)-one; C497684:Fmr1 protein, mouse