Molecular Neurodegeneration BioMed Central Review Tau exon 10 alternative splicing and tauopathies

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.

[1]  J. Tazi,et al.  Specific phosphorylation of SR proteins by mammalian DNA topoisomerase I , 1996, Nature.

[2]  J. Trojanowski,et al.  Tau-mediated neurodegeneration in Alzheimer's disease and related disorders , 2007, Nature Reviews Neuroscience.

[3]  J. Hoenicka,et al.  A New Mutation of the τ Gene, G303V, in Early-Onset Familial Progressive Supranuclear Palsy , 2005 .

[4]  R. Neve,et al.  Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. , 1986, Brain research.

[5]  K. Kosik,et al.  Competition for microtubule-binding with dual expression of tau missense and splice isoforms. , 2001, Molecular biology of the cell.

[6]  Kenneth S. Kosik,et al.  Developmentally regulated expression of specific tau sequences , 1989, Neuron.

[7]  T. Mustelin,et al.  Inhibitory Role for Dual Specificity Phosphatase VHR in T Cell Antigen Receptor and CD28-induced Erk and Jnk Activation* , 2001, The Journal of Biological Chemistry.

[8]  K. Kosik,et al.  Structure and novel exons of the human tau gene. , 1992, Biochemistry.

[9]  D L Black,et al.  Alternative pre-mRNA splicing and neuronal function. , 2003, Progress in molecular and subcellular biology.

[10]  R. Liem,et al.  Primary structure of high molecular weight tau present in the peripheral nervous system. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  R. Crowther,et al.  Pick's disease associated with the novel Tau gene mutation K369I , 2001, Annals of neurology.

[12]  M. Wilm,et al.  Protein composition of human prespliceosomes isolated by a tobramycin affinity-selection method , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[13]  K. Kosik,et al.  A tau promoter region without neuronal specificity. , 1996, Journal of neurochemistry.

[14]  K. Jellinger,et al.  The alternative splicing of tau exon 10 and its regulatory proteins CLK2 and TRA2‐BETA1 changes in sporadic Alzheimer's disease , 2006, Journal of neurochemistry.

[15]  L. Binder,et al.  Nucleolar localization of the microtubule-associated protein tau in neuroblastomas using sense and anti-sense transfection strategies. , 1997, Cell motility and the cytoskeleton.

[16]  S. Feinstein,et al.  Structural and functional differences between 3-repeat and 4-repeat tau isoforms. Implications for normal tau function and the onset of neurodegenetative disease. , 2000, The Journal of biological chemistry.

[17]  J. Lucas,et al.  Glycogen Synthase Kinase-3 Plays a Crucial Role in Tau Exon 10 Splicing and Intranuclear Distribution of SC35 , 2004, Journal of Biological Chemistry.

[18]  Michel Goedert,et al.  Mutations causing neurodegenerative tauopathies. , 2005, Biochimica et biophysica acta.

[19]  A Klug,et al.  Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Akihiko Takashima,et al.  GSK-3 is essential in the pathogenesis of Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[21]  S. Stamm,et al.  Mutations in Tau Gene Exon 10 Associated with FTDP-17 Alter the Activity of an Exonic Splicing Enhancer to Interact with Tra2β* , 2003, Journal of Biological Chemistry.

[22]  John X. Morris,et al.  Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. , 1998, Science.

[23]  Steven P. Gygi,et al.  Comprehensive proteomic analysis of the human spliceosome , 2002, Nature.

[24]  A. Krainer,et al.  Pathways for selection of 5′ splice sites by U1 snRNPs and SF2/ASF. , 1993, The EMBO journal.

[25]  Stuart C. Feinstein,et al.  Structural and Functional Differences between 3-Repeat and 4-Repeat Tau Isoforms , 2000, The Journal of Biological Chemistry.

[26]  A. Andreadis Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. , 2005, Biochimica et biophysica acta.

[27]  G. Dreyfuss,et al.  Messenger-RNA-binding proteins and the messages they carry , 2002, Nature Reviews Molecular Cell Biology.

[28]  A. Mayeda,et al.  Tra2β, SF2/ASF and SRp30c modulate the function of an exonic splicing enhancer in exon 10 of tau pre‐mRNA , 2004, Genes to cells : devoted to molecular & cellular mechanisms.

[29]  Mari Yoshida,et al.  Cellular tau pathology and immunohistochemical study of tau isoforms in sporadic tauopathies , 2006, Neuropathology : official journal of the Japanese Society of Neuropathology.

[30]  Khadija Iqbal,et al.  Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein. , 2001, The Journal of biological chemistry.

[31]  William Arbuthnot Sir Lane,et al.  A serine kinase regulates intracellular localization of splicing factors in the cell cycle , 1994, Nature.

[32]  G. Schellenberg,et al.  Determinants of 4-Repeat Tau Expression , 2000, The Journal of Biological Chemistry.

[33]  J. Hoenicka,et al.  A new mutation of the tau gene, G303V, in early-onset familial progressive supranuclear palsy. , 2005, Archives of neurology.

[34]  I. Fischer,et al.  Microtubule-associated proteins (MAPs) in the peripheral nervous system during development and regeneration , 1997, Journal of Molecular Neuroscience.

[35]  Jianhua Zhou,et al.  A minimal length between tau exon 10 and 11 is required for correct splicing of exon 10 , 2004, Journal of neurochemistry.

[36]  K. Kosik,et al.  A τ Promoter Region Without Neuronal Specificity , 1996 .

[37]  B. Graveley Sorting out the complexity of SR protein functions. , 2000, RNA.

[38]  G. Schellenberg,et al.  Regulation of tau isoform expression and dementia. , 2005, Biochimica et biophysica acta.

[39]  J. Manley,et al.  Phosphorylation–dephosphorylation differentially affects activities of splicing factor ASF/SF2 , 1998, The EMBO journal.

[40]  Y. Ihara,et al.  Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament-tau. , 1993, Journal of neurochemistry.

[41]  R. A. Crowther,et al.  Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease , 1989, Neuron.

[42]  Xiang-Dong Fu,et al.  Interplay between SRPK and Clk/Sty kinases in phosphorylation of the splicing factor ASF/SF2 is regulated by a docking motif in ASF/SF2. , 2005, Molecular cell.

[43]  J. Hodges,et al.  Tau Gene Mutation K257T Causes a Tauopathy Similar to Pick's Disease , 2000, Journal of neuropathology and experimental neurology.

[44]  M. Goedert,et al.  Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. , 1990, The EMBO journal.

[45]  A. Krainer,et al.  The Subcellular Localization of SF2/ASF Is Regulated by Direct Interaction with SR Protein Kinases (SRPKs)* , 1999, The Journal of Biological Chemistry.

[46]  Y. Ihara,et al.  τ in Paired Helical Filaments Is Functionally Distinct from Fetal τ: Assembly Incompetence of Paired Helical Filament‐τ , 1993 .

[47]  K. Kosik,et al.  Relative exon affinities and suboptimal splice site signals lead to non-equivalence of two cassette exons. , 1995, Nucleic acids research.

[48]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[49]  R. Liem,et al.  Expression of high molecular weight tau in the central and peripheral nervous systems. , 1993, Journal of cell science.

[50]  J. Hardy,et al.  Pick's disease is associated with mutations in the tau gene , 2000, Annals of neurology.

[51]  A. Delacourte,et al.  Tau protein as a differential biomarker of tauopathies. , 2005, Biochimica et biophysica acta.

[52]  M B Roth,et al.  SR proteins: a conserved family of pre-mRNA splicing factors. , 1992, Genes & development.

[53]  G. Schellenberg,et al.  Arginine/Serine-rich Protein Interaction Domain-dependent Modulation of a Tau Exon 10 Splicing Enhancer , 2006, Journal of Biological Chemistry.

[54]  E. Braak,et al.  Distribution, Levels, and Activity of Glycogen Synthase Kinase‐3 in the Alzheimer Disease Brain , 1997, Journal of neuropathology and experimental neurology.

[55]  I. Grundke‐Iqbal,et al.  Regulation of phosphorylation of tau by cyclin‐dependent kinase 5 and glycogen synthase kinase‐3 at substrate level , 2006, FEBS letters.

[56]  J. Cheng,et al.  Molecular and Genetic Studies Imply Akt-mediated Signaling Promotes Protein Kinase CβII Alternative Splicing via Phosphorylation of Serine/Arginine-rich Splicing Factor SRp40* , 2005, Journal of Biological Chemistry.

[57]  A. Krainer,et al.  Role of the Modular Domains of SR Proteins in Subnuclear Localization and Alternative Splicing Specificity , 1997, The Journal of cell biology.

[58]  R. Crowther,et al.  Cloning and sequencing of the cDNA encoding an isoform of microtubule‐associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. , 1989, The EMBO journal.

[59]  P. Lantos,et al.  Quantitative analysis of tau isoform transcripts in sporadic tauopathies. , 2005, Brain research. Molecular brain research.

[60]  G. Schellenberg,et al.  Tau is a candidate gene for chromosome 17 frontotemporal dementia , 1998, Annals of neurology.

[61]  Melissa S Jurica,et al.  Pre-mRNA splicing: awash in a sea of proteins. , 2003, Molecular cell.

[62]  A. Krainer,et al.  Multiple factors including the small nuclear ribonucleoproteins U1 and U2 are necessary for Pre-mRNA splicing in vitro , 1985, Cell.

[63]  A. Heicklen-Klein,et al.  Tau Promoter Confers Neuronal Specificity and Binds Sp1 and AP‐2 , 2000, Journal of neurochemistry.

[64]  L. Cantley,et al.  SRPK2: A Differentially Expressed SR Protein-specific Kinase Involved in Mediating the Interaction and Localization of Pre-mRNA Splicing Factors in Mammalian Cells , 1998, The Journal of cell biology.

[65]  A. Andreadis,et al.  SR protein 9G8 modulates splicing of tau exon 10 via its proximal downstream intron, a clustering region for frontotemporal dementia mutations , 2007, Molecular and Cellular Neuroscience.

[66]  T Pawson,et al.  The Clk/Sty protein kinase phosphorylates SR splicing factors and regulates their intranuclear distribution. , 1996, The EMBO journal.

[67]  D. Dickson,et al.  An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies , 2006, Acta Neuropathologica.

[68]  S. Stamm,et al.  Tau exon 10, whose missplicing causes frontotemporal dementia, is regulated by an intricate interplay of cis elements and trans factors , 2004, Journal of neurochemistry.

[69]  J. Ávila,et al.  Self assembly of microtubule associated protein tau into filaments resembling those found in Alzheimer disease. , 1986, Biochemical and biophysical research communications.

[70]  R. Crowther,et al.  Cloning of a big tau microtubule-associated protein characteristic of the peripheral nervous system. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[71]  J. Troncoso,et al.  Overexpression of four‐repeat tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer's disease , 1999, Annals of neurology.

[72]  P. Collas,et al.  Involvement of the catalytic subunit of protein kinase A and of HA95 in pre-mRNA splicing. , 2007, Experimental cell research.

[73]  Jane Y. Wu,et al.  SRp54 (SFRS11), a Regulator for tau Exon 10 Alternative Splicing Identified by an Expression Cloning Strategy , 2006, Molecular and Cellular Biology.

[74]  W. Kamphorst,et al.  Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology. , 2005, Brain : a journal of neurology.

[75]  H. Wiśniewski,et al.  Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. , 1986, The Journal of biological chemistry.

[76]  Christopher J. Lee,et al.  Alternative splicing in the nervous system: an emerging source of diversity and regulation , 2003, Biological Psychiatry.

[77]  S. Feinstein,et al.  Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau , 1994, The Journal of cell biology.