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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

Structure of exon 10 and intron 10 of tau gene. Exon 10 is shown in capital letters and part of the franking intron 9 and intron 10 are shown in lowercase. The first half of exon 10 has three exonic splicing enhancers (SC35-like, PPE and ACE). A central exon splicing silencer (ESS) separates the 5' ESE elements from a less characterized ESE at the 3'-end of exon 10. Intron 10 elements include a bipartile intronic splicing silencer (ISS) and an adjacent intronic splicing modulator (ISM). In the interface between exon 10 and intron 10, there is a stem-loop structure. Mutations that cause an increase (red), decrease (dark green) or not yet known change (black) in the ratio of 4R/3R-tau are indicated. Triangles indicate deletion mutations.
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Figure 2: Structure of exon 10 and intron 10 of tau gene. Exon 10 is shown in capital letters and part of the franking intron 9 and intron 10 are shown in lowercase. The first half of exon 10 has three exonic splicing enhancers (SC35-like, PPE and ACE). A central exon splicing silencer (ESS) separates the 5' ESE elements from a less characterized ESE at the 3'-end of exon 10. Intron 10 elements include a bipartile intronic splicing silencer (ISS) and an adjacent intronic splicing modulator (ISM). In the interface between exon 10 and intron 10, there is a stem-loop structure. Mutations that cause an increase (red), decrease (dark green) or not yet known change (black) in the ratio of 4R/3R-tau are indicated. Triangles indicate deletion mutations.

Mentions: Most alternative spliced exons contain one weak splice site. However, tau exon 10 has two weak splice sites, a weak 5' splice and a weak 3' splice site [33-35]. The exon is flanked by unusually large intron 9 (13.6 kb) and intron 10 (3.8 kb). These features of tau exon 10 lead to much complicated regulation. Several short cis-elements in exon 10 and intron 10, which modulate the use of the weak 5' and 3' splice sites, have been identified and extensively characterized [10,36]. The 5' end of exon 10 contains three ESEs: a SC35-like enhancer, a polypurine enhancer (PPE), and an A/C-rich enhancer (ACE) (Fig. 2). Following the ESEs region, there is an exon splicing silencer (ESS). In addition, the 3' end of exon 10 contains another ESE sequence between the ESS and the 5' splice site. In intron 10, there are bipartite elements composed of the ISS (E10+11 to E10+18) and the intronic splicing modulator (ISM) (E10+19 to E10+26). Deletion assay revealed opposite effects of the ISS and ISM on E10 splicing [35]. The ISM is not an enhancer by itself, but functions only in the presence of the ISS and counteracts ISS-mediated inhibition of the 5' splice site. Mutation in these elements may disrupt their function in alternative splicing of exon 10. A total of 14 mutations within the six elements (PPE, ACE, ESS, ESE, ISS and ISM) have now been identified in individuals with tauopathies. These mutations include N279K and Δ280 in PPE; L284L in ACE; N296H, N296N and Δ296N in ESS; P301S G303V in ESE; E10+11, E10+12, E10+13, E+10+14 and E10+16 in ISS; and E10+19 in ISM (Fig. 2). They all alter the alternative splicing of exon 10 by either promoting or inhibiting exon 10 inclusion.


Tau exon 10 alternative splicing and tauopathies.

Liu F, Gong CX - Mol Neurodegener (2008)

Structure of exon 10 and intron 10 of tau gene. Exon 10 is shown in capital letters and part of the franking intron 9 and intron 10 are shown in lowercase. The first half of exon 10 has three exonic splicing enhancers (SC35-like, PPE and ACE). A central exon splicing silencer (ESS) separates the 5' ESE elements from a less characterized ESE at the 3'-end of exon 10. Intron 10 elements include a bipartile intronic splicing silencer (ISS) and an adjacent intronic splicing modulator (ISM). In the interface between exon 10 and intron 10, there is a stem-loop structure. Mutations that cause an increase (red), decrease (dark green) or not yet known change (black) in the ratio of 4R/3R-tau are indicated. Triangles indicate deletion mutations.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 2: Structure of exon 10 and intron 10 of tau gene. Exon 10 is shown in capital letters and part of the franking intron 9 and intron 10 are shown in lowercase. The first half of exon 10 has three exonic splicing enhancers (SC35-like, PPE and ACE). A central exon splicing silencer (ESS) separates the 5' ESE elements from a less characterized ESE at the 3'-end of exon 10. Intron 10 elements include a bipartile intronic splicing silencer (ISS) and an adjacent intronic splicing modulator (ISM). In the interface between exon 10 and intron 10, there is a stem-loop structure. Mutations that cause an increase (red), decrease (dark green) or not yet known change (black) in the ratio of 4R/3R-tau are indicated. Triangles indicate deletion mutations.
Mentions: Most alternative spliced exons contain one weak splice site. However, tau exon 10 has two weak splice sites, a weak 5' splice and a weak 3' splice site [33-35]. The exon is flanked by unusually large intron 9 (13.6 kb) and intron 10 (3.8 kb). These features of tau exon 10 lead to much complicated regulation. Several short cis-elements in exon 10 and intron 10, which modulate the use of the weak 5' and 3' splice sites, have been identified and extensively characterized [10,36]. The 5' end of exon 10 contains three ESEs: a SC35-like enhancer, a polypurine enhancer (PPE), and an A/C-rich enhancer (ACE) (Fig. 2). Following the ESEs region, there is an exon splicing silencer (ESS). In addition, the 3' end of exon 10 contains another ESE sequence between the ESS and the 5' splice site. In intron 10, there are bipartite elements composed of the ISS (E10+11 to E10+18) and the intronic splicing modulator (ISM) (E10+19 to E10+26). Deletion assay revealed opposite effects of the ISS and ISM on E10 splicing [35]. The ISM is not an enhancer by itself, but functions only in the presence of the ISS and counteracts ISS-mediated inhibition of the 5' splice site. Mutation in these elements may disrupt their function in alternative splicing of exon 10. A total of 14 mutations within the six elements (PPE, ACE, ESS, ESE, ISS and ISM) have now been identified in individuals with tauopathies. These mutations include N279K and Δ280 in PPE; L284L in ACE; N296H, N296N and Δ296N in ESS; P301S G303V in ESE; E10+11, E10+12, E10+13, E+10+14 and E10+16 in ISS; and E10+19 in ISM (Fig. 2). They all alter the alternative splicing of exon 10 by either promoting or inhibiting exon 10 inclusion.

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