Muslimov et al. reveal how noncanonical structural motifs target RNAs to neuronal dendrites and describe how this might go awry in a neurodegenerative disease.
Many neuronal RNAs are delivered to specific locations within the nerve cell. This targeting is governed by RNA-binding proteins that often recognize the three-dimensional structure of the RNA rather than its specific nucleotide sequence. RNA structures are complex, in part because ribonucleotides aren't restricted to forming the standard “Watson-Crick” base pairs found in DNA. Noncanonical pairing between the purine bases guanine and adenine, for example, helps to form a stem-loop structure in BC1 that targets this regulatory RNA to neuronal dendrites.
Muslimov et al. found that these noncanonical base pairs were essential for the interaction of BC1 with the RNA-targeting protein hnRNP A2 and that this interaction was required for BC1’s delivery to dendrites. mRNA encoding the protein kinase PKMς relied on a similar interaction for its dendritic localization.
hnRNP A2 has also been proposed to bind stem-loop structures formed by noncanonical base pairing within the CGG repeats found in FMR1 mRNA. These CGG repeats are abnormally expanded in patients with the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Muslimov et al. found that RNA containing a high number of CGG repeats inhibited BC1’s interaction with hnRNP A2 and disrupted its delivery to dendrites, an effect reversed by increased amounts of hnRNP A2.
The repeat expansion found in FXTAS patients may thus perturb RNA targeting by competing for transport factors such as hnRNP A2. Senior author Henri Tiedge now wants to identify other RNAs that target to dendrites using noncanonical base pairing and to uncover additional proteins that interact with these motifs.