Tau isoforms which contain the domain encoded by exon 6 and their role in neurite elongation
ABSTRACT The regulation of tau protein expression during different stages of cellular differentiation and development as well as its functional role in morphogenesis, neurofibrillary tangle formation, and neurodegeneration have been topics of extensive study but have not been completely clarified yet. Tau undergoes complex regulated splicing in the mammalian nervous system. Our previous study with tau exon 6 demonstrated that it shows a splicing regulation profile which is distinct from that of the other tau exons as well as a unique expression pattern which is spatially and temporally regulated. In this study, we investigated the expression, localization, and effects of tau isoforms which contain exon 6 in neuroblastoma cells which stably overexpress them. We found that expression of one particular combination of tau exons (the longest adult isoform plus the domain of exon 6) significantly inhibits neurite elongation.
SourceAvailable from: Francisco José Fernández-Gómez[Show abstract] [Hide abstract]
ABSTRACT: Myotonic dystrophy (DM) of type 1 and 2 (DM1 and DM2) are inherited autosomal dominant diseases caused by dynamic and unstable expanded microsatellite sequences (CTG and CCTG, respectively) in the non-coding regions of the genes DMPK and ZNF9, respectively. These mutations result in the intranuclear accumulation of mutated transcripts and the mis-splicing of numerous transcripts. This so-called RNA gain of toxic function is the main feature of an emerging group of pathologies known as RNAopathies. Interestingly, in addition to these RNA inclusions, called foci, the presence of neurofibrillary tangles (NFT) in patient brains also distinguishes DM as a tauopathy. Tauopathies are a group of nearly 30 neurodegenerative diseases that are characterized by intraneuronal protein aggregates of the microtubule-associated protein Tau (MAPT) in patient brains. Furthermore, a number of neurodegenerative diseases involve the dysregulation of splicing regulating factors and have been characterized as spliceopathies. Thus, myotonic dystrophies are pathologies resulting from the interplay among RNAopathy, spliceopathy, and tauopathy. This review will describe how these processes contribute to neurodegeneration. We will first focus on the tauopathy associated with DM1, including clinical symptoms, brain histology, and molecular mechanisms. We will also discuss the features of DM1 that are shared by other tauopathies and, consequently, might participate in the development of a tauopathy. Moreover, we will discuss the determinants common to both RNAopathies and spliceopathies that could interfere with tau-related neurodegeneration.Frontiers in Molecular Neuroscience 01/2014; 6:57. DOI:10.3389/fnmol.2013.00057
Article: Tau and Tauopathies[Show abstract] [Hide abstract]
ABSTRACT: Tauopathies are age-related neurodegenerative diseases that are characterized by the presence of aggregates of abnormally phosphorylated tau. As tau was originally discovered as a microtubule-associated protein, it has been hypothesized that neurodegeneration results from a loss of the ability of tau to associate with microtubules. However, tau has been found to have other functions aside from the promotion and stabilization of microtubule assembly. It is conceivable that such functions may be affected by the abnormal phosphorylation of tau and might have consequences for neuronal function or viability. This chapter provides an overview of tau structure, functions, and its involvement in neurodegenerative diseases.Progress in molecular biology and translational science 01/2012; 107:263-93. DOI:10.1016/B978-0-12-385883-2.00004-7 · 3.11 Impact Factor
Chapter: Tau Pathology[Show abstract] [Hide abstract]
ABSTRACT: Tau pathology refers to molecular mechanisms leading to the intracellular aggregation of abnormally modified tau protein isoforms and to the propagation of this degenerating process along neuronal circuitry. Tau proteins belong to the family of microtubule-associated proteins. They are essential for the assembly of tubulin dimers into microtubules and their parallel-ordered organization. Tau is strongly expressed in neurons, localized in the axon, and is essential for neuronal architecture, plasticity, and network. From the gene to the protein, several posttranscriptional and posttranslational modifications regulate tau. At each of these levels, mechanisms can be deregulated and associated with the development of tau pathology such as in Alzheimer’s disease and in several neurologic disorders – the so-called tauopathies. In animal models, overexpression of mutated tau proteins is often used to induce a tau pathology leading to motor and/or cognitive dysfunction. Tau pathology is certainly a good therapeutic target, but untangling tau remains a major therapeutic challenge. KeywordsAlzheimer’s disease-Neurofibrillary degeneration-Microtubule-associated protein tau-Tauopathies-Tau pathology02/2011: pages 83-132;