Regulation of tau isoform expression and dementia

ArticleinBiochimica et Biophysica Acta 1739(2-3):104-15 · February 2005with8 Reads
DOI: 10.1016/j.bbadis.2004.08.009 · Source: PubMed
Abstract
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.
    • "Mutations in the MAPT gene also cause a variety of neurodegenerative phenotypes including parkinsonism. Pathogenicity of MAPT splice-site and missense mutations such as G272V, N279K, P301L, V337M and R406W were first reported to cause FTDP-17 T in 1998 (Figure 2) [48][49][50][51][52]followed by the description of many other intronic and exonic mutations (for reviews [53][54][55][56]). While most of the mutations such as P301L and N279K primarily cause familial FTD [50,57], other phenotypes such as CBD [58,59], PSP [60] and variable extent of parkinsonism have been observed in some patients and families with MAPT mutations. "
    [Show abstract] [Hide abstract] ABSTRACT: The accumulation of alpha-synuclein aggregates is the hallmark of Parkinson's disease, and more generally of synucleinopathies. The accumulation of tau aggregates however is classically found in the brains of patients with dementia, and this type of neuropathological feature specifically defines the tauopathies. Nevertheless, in numerous cases alpha-synuclein positive inclusions are also described in tauopathies and vice versa, suggesting a co-existence or crosstalk of these proteinopathies. Interestingly, alpha-synuclein and tau share striking common characteristics suggesting that they may work in concord. Tau and alpha-synuclein are both partially unfolded proteins that can form toxic oligomers and abnormal intracellular aggregates under pathological conditions. Furthermore, mutations in either are responsible for severe dominant familial neurodegeneration. Moreover, tau and alpha-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo. This suggests that interactions between tau and alpha-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration. Here, we review the recent literature with respect to elucidating the possible links between alpha-synuclein and tau.
    Full-text · Article · Oct 2014
    • "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]. "
    [Show abstract] [Hide abstract] ABSTRACT: Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are characterized by the deposition of hyperphosphorylated forms of the microtubule-associated protein tau in neurons and/or glia. This unifying pathology led to the umbrella term "tauopathies" for these conditions, also emphasizing the central role of tau in AD and FTD. Generation of transgenic mouse models expressing human tau in the brain has contributed to the understanding of the pathomechanistic role of tau in disease. To reveal the physiological functions of tau in vivo, several knockout mouse strains with deletion of the tau-encoding MAPT gene have been established over the past decade, using different gene targeting constructs. Surprisingly, when initially introduced tau knockout mice presented with no overt phenotype or malformations. The number of publications using tau knockout mice has recently markedly increased, and both behavioural changes and motor deficits have been identified in aged mice of certain strains. Moreover, tau knockout mice have been instrumental in identifying novel functions of tau, both in cultured neurons and in vivo. Importantly, tau knockout mice have significantly contributed to the understanding of the pathophysiological interplay between Aβ and tau in AD. Here, we review the literature that involves tau knockout mice to summarize what we have learned so far from depleting tau in vivo.
    Full-text · Article · Jun 2012
    • "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. "
    [Show abstract] [Hide abstract] ABSTRACT: Abnormal alternative splicing of tau exon 10 results in imbalance of 3R-tau and 4R-tau expression, which is sufficient to cause neurofibrillary degeneration. Splicing factor SC35, a member of the superfamily of the serine/arginine-rich (SR) proteins, promotes tau exon 10 inclusion. The molecular mechanism by which SC35 participates in tau exon 10 splicing remains elusive. In the present study, we found that tau pre-mRNA was coprecipitated by SC35 tagged with HA. Mutation of the SC35-like exonic splicing enhancer located at exon 10 of tau affected both the binding of SC35 to tau pre-mRNA and promotion of tau exon 10 inclusion, suggesting that SC35 acts on the SC35-like exonic splicing enhancer to promote tau exon 10 inclusion. Dyrk1A (dual-specificity tyrosine-phosphorylated and regulated kinase 1A) phosphorylated SC35 in vitro and interacted with it in cultured cells. Overexpression of Dyrk1A suppressed SC35′s ability to promote tau exon 10 inclusion. Downregulation of Dyrk1A promoted 4R-tau expression. Therefore, upregulation of Dyrk1A in Down syndrome brain or Alzheimer’s brain may cause dysregulation of tau exon 10 splicing through SC35, and probably together with other splicing factors, leading to the imbalance in 3R-tau and 4R-tau expression, which may initiate or accelerate tau pathology and cause neurofibrillary degeneration in the diseases.
    Full-text · Article · Apr 2011
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