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Published on: April 10, 2018
The role of the protein-RNA recognition code in neurodegeneration
1Institute of Chemistry, Centre for Glycomics, Slovak Academy of Sciences, Dubravska cesta 9, 84538, Bratislava, Slovak Republic. nahalka@savba.sk.
Abstract:
MicroRNAs are small endogenous RNAs that pair and bind to sites on mRNAs to direct post-transcriptional repression. However, there is a possibility that microRNAs directly influence protein structure and activity, and this influence can be termed post-translational riboregulation. This conceptual review explores the literature on neurodegenerative disorders. Research on the association between neurodegeneration and RNA-repeat toxicity provides data that support a protein-RNA recognition code. For example, this code explains why hnRNP H and SFPQ proteins, which are involved in amyotrophic lateral sclerosis, are sequestered by the (GGGGCC)n repeat sequence. Similarly, it explains why MNBL proteins and (CTG)n repeats in RNA, which are involved in myotonic dystrophy, are sequestered into RNA foci. Using this code, proteins involved in diseases can be identified. A simple protein BLAST search of the human genome for amino acid repeats that correspond to the nucleotide repeats reveals new proteins among already known proteins that are involved in diseases. For example, the (CAG)n repeat sequence, when transcribed into possible peptide sequences, leads to the identification of PTCD3, Rem2, MESP2, SYPL2, WDR33, COL23A1, and others. After confirming this approach on RNA repeats, in the next step, the code was used in the opposite manner. Proteins that are involved in diseases were compared with microRNAs involved in those diseases. For example, a reasonable correspondence of microRNA 9 and 107 with amyloid-β-peptide (Aβ42) was identified. In the last step, a miRBase search for micro-nucleotides, obtained by transcription of a prion amino acid sequence, revealed new microRNAs and microRNAs that have previously been identified as involved in prion diseases. This concept provides a useful key for designing RNA or peptide probes.
Insights
This review introduces post-translational riboregulation, where microRNAs influence protein activity. A protein-RNA recognition code helps identify disease-associated proteins and microRNAs, aiding in developing new diagnostic probes for neurodegenerative disorders.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are known regulators of gene expression via mRNA binding.
- Emerging evidence suggests miRNAs may also directly impact protein structure and function, a process termed post-translational riboregulation.
- Neurodegenerative disorders are often linked to aberrant RNA and protein interactions.
Purpose of the Study:
- To explore the concept of post-translational riboregulation in the context of neurodegenerative diseases.
- To investigate the utility of a proposed protein-RNA recognition code for identifying disease-related molecules.
- To demonstrate a novel approach for discovering potential therapeutic targets and diagnostic tools.
Main Methods:
- Literature review focusing on neurodegeneration and RNA-repeat toxicity.
- Application of a protein-RNA recognition code to identify disease-associated proteins based on amino acid and nucleotide repeat correspondences.
- Utilizing the code in reverse to correlate disease-related proteins with specific microRNAs.
- Bioinformatic analysis including protein BLAST searches and miRBase queries.
Main Results:
- The protein-RNA recognition code successfully explains protein sequestration in diseases like amyotrophic lateral sclerosis and myotonic dystrophy.
- Protein BLAST searches identified novel disease-associated proteins, such as PTCD3 and Rem2, based on (CAG)n repeat sequences.
- Correlations were found between specific microRNAs (e.g., miR-9, miR-107) and amyloid-β-peptide (Aβ42).
- Transcription of prion protein sequences identified relevant microRNAs, including those previously implicated in prion diseases.
Conclusions:
- Post-translational riboregulation is a plausible mechanism influencing protein activity.
- The protein-RNA recognition code offers a predictive framework for identifying disease-associated proteins and microRNAs.
- This conceptual approach facilitates the discovery of new molecular players in neurodegeneration and aids in designing RNA or peptide probes for diagnostics.
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