Aberrant Splicing of tau Pre-mRNA Caused by Intronic Mutations Associated with the Inherited Dementia Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17

Department of Pediatrics, Washington University in St. Louis, San Luis, Missouri, United States
Molecular and Cellular Biology (Impact Factor: 4.78). 07/2000; 20(11):4036-48. DOI: 10.1128/MCB.20.11.4036-4048.2000
Source: PubMed


Frontotemporal dementia accounts for a significant fraction of dementia cases. Frontotemporal dementia with parkinsonism linked to chromosome 17 is associated with either exonic or intronic mutations in the tau gene. This highlights the involvement of aberrant pre-mRNA splicing in the pathogenesis of neurodegenerative disorders. Little is known about the molecular mechanisms of the splicing defects underlying these diseases. To establish a model system for studying the role of pre-mRNA splicing in neurodegenerative diseases, we have constructed a tau minigene that reproduces tau alternative splicing in both cultured cells and in vitro biochemical assays. We demonstrate that mutations in a nonconserved intronic region of the human tau gene lead to increased splicing between exon 10 and exon 11. Systematic biochemical analyses indicate the importance of U1 snRNP and, to a lesser extent, U6 snRNP in differentially recognizing wild-type versus intron mutant tau pre-mRNAs. Gel mobility shift assays with purified U1 snRNP and oligonucleotide-directed RNase H cleavage experiments support the idea that the intronic mutations destabilize a stem-loop structure that sequesters the 5' splice site downstream of exon 10 in tau pre-mRNA, leading to increases in U1 snRNP binding and in splicing between exon 10 and exon 11. Thus, mutations in nonconserved intronic regions that increase rather than decrease alternative splicing can be an important pathogenic mechanism for the development of human diseases.

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    • "Thermal stability studies of oligonucleotides demonstrated that disease-associated mutations within the putative stem-loop lower the melting temperature of the RNA duplex (i.e., where the double-stranded RNA dissociates with the single-stranded form) [35, 36]. A minigene construct encoding exons 9–11 recapitulates normal tau exon 10 splicing for the wild-type sequence and increased exon 10 inclusion for disease-causing mutations [37]. This minigene has been used in our lab to demonstrate that other mutations specifically designed to enhance stability of the stem-loop (and located distal to the U1 snRNP binding site) reduce exon 10 inclusion to decrease 4R/3R as predicted [36], validating the stem-loop as a bona fide structure involved in the regulation of tau exon 10 splicing and worthy of consideration as a therapeutic target. "
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