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Tau exon 10 alternative splicing and tauopathies.

Liu F, Gong CX - Mol Neurodegener (2008)

Bottom Line: Six isoforms of tau are expressed in adult human brain, which result from alternative splicing of pre-mRNA generated from a single tau gene.Alternative splicing of tau exon 10 results in tau isoforms containing either three or four microtubule-binding repeats (3R-tau and 4R-tau, respectively).Here, we review the gene structure, transcripts and protein isoforms of tau, followed by the regulation of exon 10 splicing that determines the expression of 3R-tau or 4R-tau.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA. cxgong@mail.csi.cuny.edu.

ABSTRACT
Abnormalities of microtubule-associated protein tau play a central role in neurofibrillary degeneration in several neurodegenerative disorders that collectively called tauopathies. Six isoforms of tau are expressed in adult human brain, which result from alternative splicing of pre-mRNA generated from a single tau gene. Alternative splicing of tau exon 10 results in tau isoforms containing either three or four microtubule-binding repeats (3R-tau and 4R-tau, respectively). Approximately equal levels of 3R-tau and 4R-tau are expressed in normal adult human brain, but the 3R-tau/4R-tau ratio is altered in the brains in several tauopathies. Discovery of silence mutations and intronic mutations of tau gene in some individuals with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), which only disrupt tau exon 10 splicing but do not alter tau's primary sequence, demonstrates that dysregulation of tau exon 10 alternative splicing and consequently of 3R-tau/4R-tau balance is sufficient to cause neurodegeneration and dementia. Here, we review the gene structure, transcripts and protein isoforms of tau, followed by the regulation of exon 10 splicing that determines the expression of 3R-tau or 4R-tau. Finally, dysregulation of exon 10 splicing of tau in several tauopathies is discussed. Understanding the molecular mechanisms by which tau exon 10 splicing is regulated and how it is disrupted in tauopathies will provide new insight into the mechanisms of these tauopathies and help identify new therapeutic targets to treat these disorders.

No MeSH data available.


Related in: MedlinePlus

The gene, mRNA and protein isoforms of tau. In tau genomic structure (top panel), the black boxes represent constitutive exons, and the gray and empty boxes represent alternative spliced exons. The middle panel demonstrates mRNAs of tau in adult human brain. A total six mRNAs are generated by alternative splicing of exons 2, 3 and 10, which is indicated by alternative lines linking these exons. The lower panel shows six isoforms of tau in adult human brain. Gray boxes represent the N-terminal inserts (coded by exons 2 and 3) or MT-binding repeats (coded by exons 9, 10, 11 and 12). The second MT-binding repeat coded by exon 10 is highlighted by dark gray box. The commonly used terms for each tau isoform are listed at the right side of the isoforms.
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Figure 1: The gene, mRNA and protein isoforms of tau. In tau genomic structure (top panel), the black boxes represent constitutive exons, and the gray and empty boxes represent alternative spliced exons. The middle panel demonstrates mRNAs of tau in adult human brain. A total six mRNAs are generated by alternative splicing of exons 2, 3 and 10, which is indicated by alternative lines linking these exons. The lower panel shows six isoforms of tau in adult human brain. Gray boxes represent the N-terminal inserts (coded by exons 2 and 3) or MT-binding repeats (coded by exons 9, 10, 11 and 12). The second MT-binding repeat coded by exon 10 is highlighted by dark gray box. The commonly used terms for each tau isoform are listed at the right side of the isoforms.

Mentions: The single human tau gene is located over 100 kb on the long arm of chromosome 17 at band position 17q21.1, which contains 16 exons (Fig 1) [13,14]. Exons 1, 4, 5, 7, 9, 11, 12, and 13 are constitutive exons, and the remaining exons are subject to alternative splicing. Exon 1 is part of the promoter and is transcribed but not translated. Sequencing of the promoter region reveals a TATA-less sequence. The promoter region also contains consensus binding sites for transcription factors AP2, SP1, and GCF. The SP1-binding sites may control neuronal specific expression of tau [15,16]. Exons 4A, 6 and 8 are present in mRNA of the peripheral tissue and are never present in human brain. Exon 14 is part of the 3'untranslated region of tau mRNA [5,6]. Restriction analysis and sequencing show that tau gene contains two CpG islands, one associated with the promoter region and the other within exon 9.


Tau exon 10 alternative splicing and tauopathies.

Liu F, Gong CX - Mol Neurodegener (2008)

The gene, mRNA and protein isoforms of tau. In tau genomic structure (top panel), the black boxes represent constitutive exons, and the gray and empty boxes represent alternative spliced exons. The middle panel demonstrates mRNAs of tau in adult human brain. A total six mRNAs are generated by alternative splicing of exons 2, 3 and 10, which is indicated by alternative lines linking these exons. The lower panel shows six isoforms of tau in adult human brain. Gray boxes represent the N-terminal inserts (coded by exons 2 and 3) or MT-binding repeats (coded by exons 9, 10, 11 and 12). The second MT-binding repeat coded by exon 10 is highlighted by dark gray box. The commonly used terms for each tau isoform are listed at the right side of the isoforms.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483273&req=5

Figure 1: The gene, mRNA and protein isoforms of tau. In tau genomic structure (top panel), the black boxes represent constitutive exons, and the gray and empty boxes represent alternative spliced exons. The middle panel demonstrates mRNAs of tau in adult human brain. A total six mRNAs are generated by alternative splicing of exons 2, 3 and 10, which is indicated by alternative lines linking these exons. The lower panel shows six isoforms of tau in adult human brain. Gray boxes represent the N-terminal inserts (coded by exons 2 and 3) or MT-binding repeats (coded by exons 9, 10, 11 and 12). The second MT-binding repeat coded by exon 10 is highlighted by dark gray box. The commonly used terms for each tau isoform are listed at the right side of the isoforms.
Mentions: The single human tau gene is located over 100 kb on the long arm of chromosome 17 at band position 17q21.1, which contains 16 exons (Fig 1) [13,14]. Exons 1, 4, 5, 7, 9, 11, 12, and 13 are constitutive exons, and the remaining exons are subject to alternative splicing. Exon 1 is part of the promoter and is transcribed but not translated. Sequencing of the promoter region reveals a TATA-less sequence. The promoter region also contains consensus binding sites for transcription factors AP2, SP1, and GCF. The SP1-binding sites may control neuronal specific expression of tau [15,16]. Exons 4A, 6 and 8 are present in mRNA of the peripheral tissue and are never present in human brain. Exon 14 is part of the 3'untranslated region of tau mRNA [5,6]. Restriction analysis and sequencing show that tau gene contains two CpG islands, one associated with the promoter region and the other within exon 9.

Bottom Line: Six isoforms of tau are expressed in adult human brain, which result from alternative splicing of pre-mRNA generated from a single tau gene.Alternative splicing of tau exon 10 results in tau isoforms containing either three or four microtubule-binding repeats (3R-tau and 4R-tau, respectively).Here, we review the gene structure, transcripts and protein isoforms of tau, followed by the regulation of exon 10 splicing that determines the expression of 3R-tau or 4R-tau.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA. cxgong@mail.csi.cuny.edu.

ABSTRACT
Abnormalities of microtubule-associated protein tau play a central role in neurofibrillary degeneration in several neurodegenerative disorders that collectively called tauopathies. Six isoforms of tau are expressed in adult human brain, which result from alternative splicing of pre-mRNA generated from a single tau gene. Alternative splicing of tau exon 10 results in tau isoforms containing either three or four microtubule-binding repeats (3R-tau and 4R-tau, respectively). Approximately equal levels of 3R-tau and 4R-tau are expressed in normal adult human brain, but the 3R-tau/4R-tau ratio is altered in the brains in several tauopathies. Discovery of silence mutations and intronic mutations of tau gene in some individuals with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), which only disrupt tau exon 10 splicing but do not alter tau's primary sequence, demonstrates that dysregulation of tau exon 10 alternative splicing and consequently of 3R-tau/4R-tau balance is sufficient to cause neurodegeneration and dementia. Here, we review the gene structure, transcripts and protein isoforms of tau, followed by the regulation of exon 10 splicing that determines the expression of 3R-tau or 4R-tau. Finally, dysregulation of exon 10 splicing of tau in several tauopathies is discussed. Understanding the molecular mechanisms by which tau exon 10 splicing is regulated and how it is disrupted in tauopathies will provide new insight into the mechanisms of these tauopathies and help identify new therapeutic targets to treat these disorders.

No MeSH data available.


Related in: MedlinePlus