Regulation of tau isoform expression and dementia

Department of Medicine , University of Washington Seattle, Seattle, Washington, United States
Biochimica et Biophysica Acta (Impact Factor: 4.66). 02/2005; 1739(2-3):104-15. DOI: 10.1016/j.bbadis.2004.08.009
Source: PubMed


In the central nervous system (CNS), aberrant changes in tau mRNA splicing and consequently in protein isoform ratios cause abnormal aggregation of tau and neurodegeneration. Pathological tau causes neuronal loss in Alzheimer's disease (AD) and a diverse group of disorders called the frontotemporal dementias (FTD), which are two of the most common forms of dementia and afflict more than 10% of the elderly population. Autosomal dominant mutations in the tau gene cause frontotemporal dementia with parkinsonism-chromosome 17 type (FTDP-17). Just over half the mutations affect tau protein function and decrease its affinity for microtubules (MTs) or increase self-aggregation. The remaining mutations occur within exon 10 (E10) and intron 10 sequences and alter complex regulation of E10 splicing by multiple mechanisms. FTDP-17 splicing mutations disturb the normally balanced levels of distinct protein isoforms that result in altered biochemical and structural properties of tau. In addition to FTDP-17, altered tau isoform levels are also pathogenically associated with other FTD disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration and Pick's disease; however, the mechanisms remain undefined and mutations in tau have not been detected. FTDP-17 highlights the association between splicing mutations and the pronounced variability in pathology as well as phenotype that is characteristic of inherited disorders.

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    • "While 3R isoforms are predominant during embryonic brain development, the normal adult brain has approximately equal levels of 3R and 4R isoforms [17]. Changes in this ratio have been linked to the pathogenesis of tauopathies, with increased 4R levels in AD and high amounts of 3R tau in PiD [18]. For comparison, mice and rats express only three different 4R isoforms of tau, but lack 3R tau [19]. "
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    • "Previous studies reported that the extent of SC35 recruitment to alternatively spliced transcripts of tau exon 10 is related to exon 10 inclusion (19). Tau exon 10 contains a SC35-like enhancer at 5′-end (20,21). However, there is no direct evidence that SC35 acts on SC35-like enhancer to promote tau exon 10 inclusion. "
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    • "In peripheral lymphocytes from the patient, the deleted allele of the MAPT gene was transcribed and alternative splicing of exon 10 was conserved. This is consistent with the finding that regulation of alternative splicing of exon 10 involves elements located in exon 10 itself and in the intron following exon 10, as well as the polypyrimidine tract just preceding exon 10 (D'Souza and Schellenberg 2005; Malkani et al., 2006). As a result, two sets of isoforms, both lacking the first MT binding domain are predicted to be produced (2R-or 3R-tauΔ6-9). "
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