Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486

Dolan B.M.; Duron S.G.; Campbell D.A.Vollrath B.Shankaranarayana Rao B.S.Ko H.-Y.Lin G.G.Govindarajan A.Choi S.-Y.Tonegawa S.

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Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486

机译：Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486

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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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第14期|5671-5676|共6页
作者
Dolan B.M.; Duron S.G.; Campbell D.A.Vollrath B.Shankaranarayana Rao B.S.Ko H.-Y.Lin G.G.Govindarajan A.Choi S.-Y.Tonegawa S.;
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作者单位

Picower Institute for Learning and Memory, RIKEN-MIT Center for Neural Circuit Genetics, Department of Biology, Cambridge, MA 02139, United States;

Afraxis, Inc., San Diego, CA 92037, United States;

Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, IndiaDepartment of Physiology, Seoul National University, School of Dentistry, Seoul 110-749, South Korea;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Drug discovery; Neurodevelopmental disorder;

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486

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