MicroRNA-277 modulates the neurodegeneration caused by fragile X premutation rCGG repeats

Fragile x-associated tremor/ataxia syndrome (fxtas),a late-onset neurodegenerative disorder,has been recognized in older male fragile x premutation carriers and is uncoupled from fragile x syndrome. using a drosophila model of fxtas,we previously showed that transcribed premutation repeats alone are sufficient to cause neurodegeneration. mirnas are sequence-specific regulators of post-transcriptional gene expression. to determine the role of mirnas in rcgg repeat-mediated neurodegeneration,we profiled mirna expression and identified selective mirnas,including mir-277,that are altered specifically in drosophila brains expressing rcgg repeats. we tested their genetic interactions with rcgg repeats and found that mir-277 can modulate rcgg repeat-mediated neurodegeneration. furthermore,we identified drep-2 and vimar as functional targets of mir-277 that could modulate rcgg repeat-mediated neurodegeneration. finally,we found that hnrnp a2/b1,an rcgg repeat-binding protein,can directly regulate the expression of mir-277. these results suggest that sequestration of specific rcgg repeat-binding proteins could lead to aberrant expression of selective mirnas,which may modulate the pathogenesis of fxtas by post-transcriptionally regulating the expression of specific mrnas involved in fxtas. © 2012 tan et al.