Hyperactive locomotion in a Drosophila model is a functional readout for the synaptic abnormalities underlying fragile X syndrome

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Science Signaling  02 May 2017:
Vol. 10, Issue 477, eaai8133
DOI: 10.1126/scisignal.aai8133

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Spurring drug development for FXS

Fragile X syndrome (FXS) is an autistic intellectual disability disorder caused by loss of the RNA binding protein FMRP. Treating FXS has been challenging because of the lack of a reliable in vivo drug screening model. Kashima et al. found that the hyperactive locomotion observed in a fly model of FXS was a reliable behavioral marker for the neurological abnormalities underlying the disease. The kinase LIMK1 is implicated in the pathogenesis of FXS, and high-throughput (rapid, quantitative, and time- and cost-effective) drug screening in the fly FXS model confirmed that LIMK1 inhibitors ameliorated both the neurological and behavioral phenotypes of this model. LIMK1 inhibitors also reduced hyperactivity in a mouse model of FXS. Thus, this method may aid in future drug development for FXS patients.


Fragile X syndrome (FXS) is the most common cause of heritable intellectual disability and autism and affects ~1 in 4000 males and 1 in 8000 females. The discovery of effective treatments for FXS has been hampered by the lack of effective animal models and phenotypic readouts for drug screening. FXS ensues from the epigenetic silencing or loss-of-function mutation of the fragile X mental retardation 1 (FMR1) gene, which encodes an RNA binding protein that associates with and represses the translation of target mRNAs. We previously found that the activation of LIM kinase 1 (LIMK1) downstream of augmented synthesis of bone morphogenetic protein (BMP) type 2 receptor (BMPR2) promotes aberrant synaptic development in mouse and Drosophila models of FXS and that these molecular and cellular markers were correlated in patients with FXS. We report that larval locomotion is augmented in a Drosophila FXS model. Genetic or pharmacological intervention on the BMPR2-LIMK pathway ameliorated the synaptic abnormality and locomotion phenotypes of FXS larvae, as well as hyperactivity in an FXS mouse model. Our study demonstrates that (i) the BMPR2-LIMK pathway is a promising therapeutic target for FXS and (ii) the locomotion phenotype of FXS larvae is a quantitative functional readout for the neuromorphological phenotype associated with FXS and is amenable to the screening novel FXS therapeutics.

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