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Structural determinants for alternative splicing regulation of the MAPT pre-mRNA.
RNA Biol 2015; 12(3):330-42RB

Abstract

Alternative splicing at the MAPT gene exon 10 yields similar levels of the 3R and 4R tau protein isoforms. (1) The presence of mutations, particularly in exon 10 and intron 10-11, changes the quantity of tau isoforms. Domination each of the isoform yields tau protein aggregation and frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Here, we report for the first time the secondary structure of the 194/195 nucleotide region for the wild type (WT) and 10 mutants of the MAPT gene pre-mRNA determined using both chemical and microarray mapping. Thermodynamic analyses indicate that single nucleotide mutations in the splicing regulatory element (SRE) that form a hairpin affect its stability by up to 4 and 7 kcal/mol. Moreover, binding the regulatory hairpin of small molecule ligands (neomycin, kanamycin, tobramycin and mitoxantrone) enhance its stability depending on the nature of the ligands and the RNA mutations. Experiments using the cos-7 cell line indicate that the presence of ligands and modified antisense oligonucleotides affect the quantity of 3R and 4R isoforms. This finding correlates with the thermodynamic stability of the regulatory hairpin. An alternative splicing regulation mechanism for exon 10 is postulated based on our experimental data and on published data.

Authors+Show Affiliations

a Institute of Bioorganic Chemistry; Polish Academy of Sciences ; Noskowskiego, Poland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25826665

Citation

Lisowiec, Jolanta, et al. "Structural Determinants for Alternative Splicing Regulation of the MAPT Pre-mRNA." RNA Biology, vol. 12, no. 3, 2015, pp. 330-42.
Lisowiec J, Magner D, Kierzek E, et al. Structural determinants for alternative splicing regulation of the MAPT pre-mRNA. RNA Biol. 2015;12(3):330-42.
Lisowiec, J., Magner, D., Kierzek, E., Lenartowicz, E., & Kierzek, R. (2015). Structural determinants for alternative splicing regulation of the MAPT pre-mRNA. RNA Biology, 12(3), pp. 330-42. doi:10.1080/15476286.2015.1017214.
Lisowiec J, et al. Structural Determinants for Alternative Splicing Regulation of the MAPT Pre-mRNA. RNA Biol. 2015;12(3):330-42. PubMed PMID: 25826665.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural determinants for alternative splicing regulation of the MAPT pre-mRNA. AU - Lisowiec,Jolanta, AU - Magner,Dorota, AU - Kierzek,Elzbieta, AU - Lenartowicz,Elzbieta, AU - Kierzek,Ryszard, PY - 2015/4/1/entrez PY - 2015/4/1/pubmed PY - 2015/12/19/medline KW - AD, Alzheimer disease KW - DMS, dimethyl sulfide KW - ESE, exonic splicing enhancer KW - ESS, exonic splicing silencer KW - FTD, frontotemporal dementia KW - FTDP-17, frontotemporal dementia and Parkinsonism linked to chromosome 17 KW - ISM, intronic splicing modulator KW - ISS, intronic splicing silencer KW - MAPT, microtubule-associated protein tau KW - NMIA, N-methylisotoic anhydride KW - NMR, nuclear magnetic resonance KW - PPE, polypurine enhancer KW - RNA structure KW - RNA thermodynamics KW - RT-PCR, reverse transcription polymerase chain reaction KW - SHAPE, selective 2′-hydroxyl acylation analyzed by primer extension KW - SMA, spinal muscular atrophy KW - SRE, splicing regulatory element KW - U1 snRNP, U1 small nuclear ribonucleoprotein KW - WT, wild type KW - alternative splicing regulation KW - antisense oligonucleotides KW - neurodegradation KW - pre-mRNA, pre-messenger RNA KW - small molecule binding SP - 330 EP - 42 JF - RNA biology JO - RNA Biol VL - 12 IS - 3 N2 - Alternative splicing at the MAPT gene exon 10 yields similar levels of the 3R and 4R tau protein isoforms. (1) The presence of mutations, particularly in exon 10 and intron 10-11, changes the quantity of tau isoforms. Domination each of the isoform yields tau protein aggregation and frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Here, we report for the first time the secondary structure of the 194/195 nucleotide region for the wild type (WT) and 10 mutants of the MAPT gene pre-mRNA determined using both chemical and microarray mapping. Thermodynamic analyses indicate that single nucleotide mutations in the splicing regulatory element (SRE) that form a hairpin affect its stability by up to 4 and 7 kcal/mol. Moreover, binding the regulatory hairpin of small molecule ligands (neomycin, kanamycin, tobramycin and mitoxantrone) enhance its stability depending on the nature of the ligands and the RNA mutations. Experiments using the cos-7 cell line indicate that the presence of ligands and modified antisense oligonucleotides affect the quantity of 3R and 4R isoforms. This finding correlates with the thermodynamic stability of the regulatory hairpin. An alternative splicing regulation mechanism for exon 10 is postulated based on our experimental data and on published data. SN - 1555-8584 UR - https://www.unboundmedicine.com/medline/citation/25826665/Structural_determinants_for_alternative_splicing_regulation_of_the_MAPT_pre_mRNA_ L2 - http://www.tandfonline.com/doi/full/10.1080/15476286.2015.1017214 DB - PRIME DP - Unbound Medicine ER -