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Review
. 2015 Jul 1;87(1):28-46.
doi: 10.1016/j.neuron.2015.06.012.

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

Viachaslau Bernat  1 , Matthew D Disney  2
Affiliations
Review

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

Viachaslau Bernat et al. Neuron. .

Abstract

RNAs adopt diverse folded structures that are essential for function and thus play critical roles in cellular biology. A striking example of this is the ribosome, a complex, three-dimensionally folded macromolecular machine that orchestrates protein synthesis. Advances in RNA biochemistry, structural and molecular biology, and bioinformatics have revealed other non-coding RNAs whose functions are dictated by their structure. It is not surprising that aberrantly folded RNA structures contribute to disease. In this Review, we provide a brief introduction into RNA structural biology and then describe how RNA structures function in cells and cause or contribute to neurological disease. Finally, we highlight successful applications of rational design principles to provide chemical probes and lead compounds targeting structured RNAs. Based on several examples of well-characterized RNA-driven neurological disorders, we demonstrate how designed small molecules can facilitate the study of RNA dysfunction, elucidating previously unknown roles for RNA in disease, and provide lead therapeutics.

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Figures

Figure 1
Figure 1
Number of high-resolution structures containing RNA molecules deposited in PDB database per year since 1991. Source: PDB database http://www.rcsb.org (Berman et al., 2000).
Figure 2
Figure 2
Secondary structural elements found in RNA and the 3D structure of the ribosome. A) Schematics of secondary structural elements in RNA and representative three-dimensional structures from PDB. Nucleobases involved in Watson-Crick base pairing or G-quadruplexes are colored aquamarine and green; other bases are colored magenta. PDB IDs for 3D structures: stem-loop – 4TV0 (Zhang et al., 2014), internal loop – 2L8F (Lerman et al., 2011), bulge – 1AJL (Luebke et al., 1997), pseudo-knot – 2A43 (Pallan et al., 2005), G-quadruplex – 2KBP (Martadinata and Phan, 2009). B) Model of eukaryotic translation initiation complex. Proteins and mRNA have been removed for clarity. Individual RNA chains are represented in different colors (Voigts-Hoffmann et al., 2012). Downloaded and adapted from https://www.mol.biol.ethz.ch/groups/ban_group/Initiation. Structures are rendered with PyMOL (Schrödinger LLC, 2010).
Figure 3
Figure 3
Structure of splicing-regulating proteins MBNL1 and NOVA in complex with RNA recognition elements and location of splice sites in corresponding mRNAs. A) Fragment of MBNL1 complexed with a canonical recognition sequence of RNA, GCUGU, PDB ID 3D2S (Teplova and Patel, 2008). B) Fragment of NOVA1 complexed with a stem-loop of a cognate RNA, PDB ID 2ANN (Teplova et al., 2011). C) Locations of RNA recognition sites for MBNL1 and NOVA1, relative to alternatively spliced exons. Representative mRNA substrates are listed next to arrows denoting the RNA recognition element location (Konieczny et al., 2014; Ule et al., 2006). cTNT, cardiac troponin T, CLCN1, muscle-specific chloride ion channel 1; GABRG2, γ-aminobutyric acid (GABA) receptor γ2; GLRA2, glycine receptor α2; INSR, insulin receptor; KCNMA1, potassium large conductance calcium-activated channel, subfamily M, α1; MBNL1, muscleblind-like protein 1; NOVA1, neuro-oncological ventral antigen 1
Figure 4
Figure 4
RNA structure prediction and chemical mapping. A) Phylogenetic analysis of three sequences highlighting conserved base paired regions (green) and mismatches (yellow). B) Two alternative structures predicted for sequence 3 by RNAstructure (Reuter and Mathews, 2010). Red arrows indicate locations of reactive hydroxyl groups identified by 2′-hydroxyl acylation and primer extension (SHAPE). Blue asterisks indicate A and C residues susceptible for methylation by dimethyl sulfate (DMS). C) Chemical reactions underlying SHAPE and DMS mapping. 1M7 is 1-methyl-7-nitroisatoic anhydride.
Figure 5
Figure 5
Representative functions of structured non-coding RNAs in cells. A) Schematic of a triplex formed between DNA and lncRNA that allosterically recruits gene-regulating proteins. B) Simplified representation of SRP RNA’s role in targeting membrane proteins to the endoplasmic reticulum (ER) for their proper folding. C) Schematic of co-transcriptional cleavage element regulating transcription termination of the β-globin gene. CoTC, co-transcriptional cleavage element; ER, endoplasmic reticulum; RNA Pol II, RNA polymerase II; SRP, signal recognition particle
Figure 6
Figure 6
Targeting expanded repeating RNAs that cause or contribute to microsatellite disorders. A) Two-dimensional representation of a hairpin with multiple internal loops formed by expanded microsatellite repeats with examples of repetitive nucleotide sequences. B) Three-dimensional structure of r(CGG)3 fragment, PDB ID 3SJ2 (Kumar et al., 2011b). Coloring scheme is the same as for Figure 2. C) Targeting repetitive structural elements with small molecules, modularly assembled multivalent binders with increased affinity and selectivity, and in cellulo oligomerization as an ultimate strategy for precise targeting of expanded RNA repeats.
Figure 7
Figure 7
Secondary structure of the hairpin that regulates the alternative splicing of exon 10 in microtubule-associated protein tau (MAPT) pre-mRNA. Hairpin mutants are arranged in order of decreasing thermodynamic stability (left to right), according to published data (Donahue et al., 2006; Varani et al., 1999). Mutations increasing the number of intramolecular hydrogen bonds are highlighted in blue; mutations decreasing the number of Watson-Crick base pairs are highlighted in red. Exon nucleotides are highlighted in green. The bulge targeted by small molecules is boxed in red in the wild type (WT) hairpin (see main text for details). Mutations, which deregulate normal splicing of MAPT leading to frontotemporal dementia and Parkinsonism associated with chromosome 17 (FTDP-17), are underlined.
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