Editors' ChoiceNeuroscience

New connections: Treating fragile X syndrome

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Science Signaling  02 May 2017:
Vol. 10, Issue 477, eaan5441
DOI: 10.1126/scisignal.aan5441

An in vivo drug screen can identify inhibitors of the signaling pathway that is activated in fragile X syndrome.

Fragile X syndrome (FXS) is the most common genetic cause of autism and intellectual disability and is characterized by abnormal synaptic structures in neurons. FXS is caused by loss of expression of the gene encoding the RNA binding protein FMRP, which suppresses the translation of various mRNAs. Two papers from the Hata laboratory published in Science Signaling reveal a molecular mechanism in fragile X syndrome and describe the development of a drug screen in an animal model of the disease.

Kashima et al. (2016) reported that the loss of FMRP in fruit flies and mice increased the abundance of the bone morphogenetic protein type II receptor (BMPR2) and activated a downstream kinase LIMK1 in neurons, which impaired actin polymerization and spine development (see also the Focus by Broihier). These molecular markers were also detected in postmortem brain tissue from FXS patients. Reducing signaling through the BMPR2-LIMK1 pathway suppressed abnormal dendritic spine growth in FXS model mice, suggesting that this might be a therapeutic option for FXS patients.

However, treating FXS has been challenging because of the lack of a consistent or quantifiable preclinical in vivo model, particularly with which to screen potential drug therapies. Kashima et al. (2017) found that the hyperactive locomotion observed in FXS fly larvae was a reliable behavioral marker for the neurological abnormalities underlying the disease. They then developed open-source software called LarvaTrack that uses a cell phone video camera to record and quantify locomotion of multiple larvae simultaneously, resulting in a high-throughput, inexpensive, and quantitative in vivo drug screen. Analysis of larval locomotion by LarvaTrack confirmed that LIMK1 inhibitors ameliorated both the neurological and behavioral phenotypes in this fly model. Furthermore, these drugs reduced hyperactivity in a mouse model of FXS. The authors’ discoveries not only show that LIMK1 is a promising therapeutic target for FXS but also may aid future drug development for FXS patients.

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