DOI work
Fetched
Post
crossref
Bridget M. Dolan, Sergio G. Duron, David A. Campbell, Benedikt Vollrath, B. S. Shankaranarayana Rao, Hui-Yeon Ko, Gregory G. Lin, Arvind Govindarajan, et al.
(2013).
Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486.
Proceedings of the National Academy of Sciences, 110(14), 5671-5676.
National Academy of Sciences.
- Publication date
-
18 Mar 2013
- Identifier
-
10.1073/pnas.1219383110
- Authors
-
Bridget M. Dolan,
Sergio G. Duron,
David A. Campbell,
Benedikt Vollrath,
B. S. Shankaranarayana Rao,
Hui-Yeon Ko,
Gregory G. Lin,
Arvind Govindarajan,
Se-Young Choi,
Susumu Tonegawa
- Source
- Proceedings of the National Academy of Sciences
- Details
- 110(14), 5671-5676
- Reference type
- article
- Publisher
- National Academy of Sciences
- Metadata source
- crossref
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.
Study authors in this cited reference