title: Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice.
abstract: Fragile X syndrome (FXS), the most commonly inherited form of mental retardation and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene and consequent loss of the fragile X mental retardation protein. Despite growing evidence suggesting a role of specific receptors and biochemical pathways in FXS pathogenesis, an effective therapeutic method has not been developed. Here, we report that abnormalities in FMR1 knockout (KO) mice, an animal model of FXS, are ameliorated, at least partially, at both cellular and behavioral levels, by an inhibition of the catalytic activity of p21-activated kinase (PAK), a kinase known to play a critical role in actin polymerization and dendritic spine morphogenesis. Greater spine density and elongated spines in the cortex, morphological synaptic abnormalities commonly observed in FXS, are at least partially restored by postnatal expression of a dominant negative (dn) PAK transgene in the forebrain. Likewise, the deficit in cortical long-term potentiation observed in FMR1 KO mice is fully restored by the dnPAK transgene. Several behavioral abnormalities associated with FMR1 KO mice, including those in locomotor activity, stereotypy, anxiety, and trace fear conditioning are also ameliorated, partially or fully, by the dnPAK transgene. Finally, we demonstrate a direct interaction between PAK and fragile X mental retardation protein in vitro. Overall, our results demonstrate the genetic rescue of phenotypes in a FXS mouse model and suggest that the PAK signaling pathway, including the catalytic activity of PAK, is a novel intervention site for development of an FXS and autism therapy.
authors.affiliation: The Picower Institute for Learning and Memory, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Mansuo L
authors.initials: ML
authors.lastname: Hayashi
authors.forename: B S Shankaranarayana
authors.initials: BS
authors.lastname: Rao
authors.forename: Jin-Soo
authors.initials: JS
authors.lastname: Seo
authors.forename: Han-Saem
authors.initials: HS
authors.lastname: Choi
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Dolan
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Sumantra
authors.initials: S
authors.lastname: Chattarji
authors.forename: Susumu
authors.initials: S
authors.lastname: Tonegawa
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D049229:Dendritic Spines / Q000201:enzymology / Q000235:genetics; D004195:Disease Models, Animal; D005600:Fragile X Syndrome / Q000201:enzymology* / Q000235:genetics* / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D054462:p21-Activated Kinases
chemical_list: C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases