The RNA encoding the microtubule-associated protein tau has extensive structure that affects its biology

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.

Genetic mutations of APOEε4 carriers in cardiovascular patients lead to the development of insulin resistance and risk of Alzheimer's disease

“…In the human brain, the major tau protein is encoded by 11-axons. [19] When the tau protein is linked with α and β globulin, its function is to maintain the microtubule stability. This microtubule stability in neurons is further essential for maintenance of synaptic plasticity, axonal transport, and neuronal structure.…”

Quantitative prediction of variant effects on alternative splicing in MAPT using endogenous pre-messenger RNA structure probing

“…RNA structure around exon-intron junctions has been shown to regulate alternative splicing ( Warf and Berglund, 2010 ; Buratti and Baralle, 2004 ), and a hairpin structure at the exon 10 – intron 10 junction of MAPT pre-mRNA is implicated in establishing the 3R to 4R 1:1 isoform ratio ( Hutton et al, 1998 ; Varani et al, 1999 ; Grover et al, 1999 ; Donahue et al, 2006 ). The structure of the MAPT pre-mRNA in the exon 10 – intron 10 junction region has been studied using biophysical techniques and chemical probing of in vitro-transcribed fragments and using computational methods ( Varani et al, 1999 ; Lisowiec et al, 2015 ; Tan et al, 2019 ; Chen et al, 2019 ), but the pre-mRNA structure had not previously been analyzed in cells. We obtained DMS-MaP data for this junction from endogenous pre-mRNA in T47D cells ( Figure 2A ).…”

What’s in a Gene? The Outstanding Diversity of MAPT

“…The regulation of these splicing events is complex and involves the orchestration of a myriad of splicing factors, including Serine-rich splicing factors (SRSF1, 2, 3, 4, 6, 7 and 9) [ 34 , 39 ] and the arginine and serine-rich coiled coil protein (RSRC1) [ 40 ], but also non-SR proteins, such as RNA-binding motif protein 4 (RBM4) [ 34 ] and 11 (RBM11) [ 40 ], RNA helicase p68, heterogeneous nuclear ribonucleoproteins (hnRNP) [ 41 ] or Tra2β, among others [ 34 , 39 ]. Such regulation is still more intricated, considering the Tau splicing depends upon developmental stage and tissue type [ 9 ], the modulation of the activity of such factors [ 34 ] and the existence of different RNA structures that can influence MAPT mRNA stability and splicing [ 42 ]. The complexity of regulation of MAPT splicing highlights the need of finely tuned mechanisms that ensure the correct and precise modulation of the processes that encompass such splicing [ 40 , 41 ].…”