Abstract
Tauopathies are neurodegenerative diseases that affect millions of people worldwide including those with Alzheimer’s disease. While many efforts have focused on understanding the role of tau protein in neurodegeneration, there has been little done to systematically analyze and study the structures within tau’s encoding RNA and their connection to disease pathology. Knowledge of RNA structure can provide insights into disease mechanisms and how to affect protein production for therapeutic benefit. Using computational methods based on thermodynamic stability and evolutionary conservation, we identified structures throughout the tau pre-mRNA, especially at exon-intron junctions and within the 5′ and 3′ untranslated regions (UTRs). In particular, structures were identified at twenty exon-intron junctions. The 5′ UTR contains one structured region, which lies within a known internal ribosome entry site. The 3′ UTR contains eight structured regions, including one that contains a polyadenylation signal. A series of functional experiments were carried out to assess the effects of mutations associated with mis-regulation of alternative splicing of exon 10 and to identify regions of the 3′ UTR that contain cis-regulatory elements. These studies defined novel structural regions within the mRNA that affect stability and pre-mRNA splicing and may lead to new therapeutic targets for treating tau-associated diseases.
Highlights
Tauopathies are a class of neurodegenerative diseases characterized by the presence of tau inclusion bodies.[7]
That compared to random sequences, the minimum free energy (MFE) ΔG° of functional RNAs is lower.[40]. This is attributed to the evolved order and composition of functional RNAs, which require structure to function; disrupting this ordered sequence disrupts stabilizing base pairs leading to less favorable ΔG° values
Two folds were predicted at the exon 2-intron 2 junction, the larger of which is an extended form of a hairpin where the stem contains two single nucleotide bulges
Summary
Tauopathies are a class of neurodegenerative diseases characterized by the presence of tau inclusion bodies.[7]. Tau proteins bind to and stabilize microtubules via their MBD repeat sequences that interact with negatively charged tubulin residues via their net positive charge.[9] Alterations in the protein coding content of the mRNA, including the number of MBDs, are due to alternative splicing. Structured regions were identified at exon-intron junctions and within the long 3′ UTR isoform that may control tau expression. This method may be applied to diseases, such as tauopathies, in which RNA dysfunction contributes to disease development. Knowledge of RNA structure in the MAPT gene may lead to new therapeutics against RNA, such as small molecules for treatment of tauopathies.[19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
