Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17 (original) (raw)
Related papers
Acta Neuropathologica, 2006
Defective splicing of tau mRNA, promoting a shift between tau isoforms with (4R tau) and without (3R tau) exon 10, is believed to be a pathological consequence of certain tau mutations causing frontotemporal dementia. By assessing protein and mRNA levels of 4R tau and 3R tau in 27 AD and 20 control temporal cortex, we investigated whether altered tau splicing is a feature also in Alzheimer's disease (AD). However, apart from an expected increase of sarcosyl-insoluble tau in AD, there were no signiWcant diVerences between the groups. Next, by laser-capture microscopy and quantitative PCR, we separately analyzed CA1 hippocampal neurons with and without neuroWbrillary pathology from six of the AD and seven of the control brains. No statistically signiWcant diVerences in 4R tau/ 3R tau mRNA were found between the diVerent subgroups. Moreover, we conWrmed the absence of signiWcant ratio diVerences in a second data set with lasercaptured entorhinal cortex neurons from four AD and four control brains. Finally, the 4R tau/3R tau ratio in CA1 neurons was roughly half of the ratio in temporal cortex, indicating region-speciWc diVerences in tau mRNA splicing. In conclusion, this study indicated region-speciWc and possibly cell-type-speciWc tau splicing but did not lend any support to overt changes in alternative splicing of tau exon 10 being an underlying factor in AD pathogenesis.
Regulation of Alternative Splicing of Human Tau Exon 10 by Phosphorylation of Splicing Factors
Molecular and Cellular Neuroscience, 2001
Tau is a microtubule-associated protein whose transcript undergoes regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and encodes a microtubule-binding domain. Mutations increasing the inclusion of exon 10 result in the production of tau protein which predominantly contains four microtubule-binding repeats and were shown to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Here we show that exon 10 usage is regulated by CDC2-like kinases CLK1, 2, 3, and 4 that phosphorylate serine-arginine-rich proteins, which in turn regulate pre-mRNA splicing. Cotransfection experiments suggest that CLKs achieve this effect by releasing specific proteins from nuclear storage sites. Our results show that changing pre-mRNA-processing pathways through phosphorylation could be a new therapeutic concept for tauopathies. 3 Abbreviations used: FTDP-17, frontotemporal dementia and parkinsonism linked to chromosome 17; DARPP-32, dopamine and cyclic AMP-regulated phosphoprotein, relative molecular mass 32,000; SR protein, serine-arginine-rich protein.
Molecular Brain Research, 1999
The microtubule-associated protein tau regulates the dynamic stability of the neuronal cytoskeleton by interacting with microtubules. It is encoded by a single gene, but expressed in a variety of isoforms due to differential RNA splicing. Six isoforms can be found in the human central nervous system. These isoforms differ in their ability to promote the assembly of microtubules as well as in their capacity to stabilize existing microtubule structures. Furthermore, some of the isoforms of tau are specifically involved in the pathogenesis of neurodegenerative disorders. Thus, splicing of tau might critically influence the physiological functions of tau protein as well as the pathogenesis of neurodegenerative diseases with tauopathy. The present study addresses the differential expression of the six isoforms of tau in the central nervous system of 12 mammalian species including Homo sapiens. The occurrence of each of the six tau isoforms was highly variable. However, species that were phylogenetically related expressed a similar pattern of tau isoforms. These results suggest a phylogenetic descent of splicing paradigms, which can be matched with known phylogenetic concepts based on morphological and molecular genetical studies. Especially, the unique expression pattern of tau isoforms in the human central nervous system implicates a possible link to the particular vulnerability of humans to neurodegenerative disorders with tauopathy, namely Alzheimer's disease, frontotemporal dementia and Pick's disease.
A novel mutation at position +11 in the intron following exon 10 of the tau gene in FTDP-17
Journal of applied genetics, 2002
Mutations in the microtubule-associated tau gene are responsible for frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). A reduced ability of the mutated microtubule-associated tau protein to interact with microtubules causes microtubule destabilization leading to deleterious effects on axonal transport and the formation of tau filaments. Here, we describe a new mutation of the tau gene, a T --> C transition at position +11 of the intron following exon 10 (T --> C 3'E10 +11) in the family showing frontotemporal dementia with very early age of onset (the first decade of proband's life). The T -->C 3'E10 +11 mutation caused a large increase in the proportion of transcripts containing exon 10 detected by exon-trapping analysis. Our study confirmed that the T --> C 3'E10 +11 mutation, as the other 5' splice site mutations of tau exon 10, modifies alternative splicing of exon 10.
Cell reports, 2018
The microtubule-associated protein tau regulates myriad neuronal functions, such as microtubule dynamics, axonal transport and neurite outgrowth. Tauopathies are neurodegenerative disorders characterized by the abnormal metabolism of tau, which accumulates as insoluble neuronal deposits. The adult human brain contains equal amounts of tau isoforms with three (3R) or four (4R) repeats of microtubule-binding domains, derived from the alternative splicing of exon 10 (E10) in the tau transcript. Several tauopathies are associated with imbalances of tau isoforms, due to splicing deficits. Here, we used a trans-splicing strategy to shift the inclusion of E10 in a mouse model of tauopathy that produces abnormal excess of 3R tau. Modulating the 3R/4R ratio in the prefrontal cortex led to a significant reduction of pathological tau accumulation concomitant with improvement of neuronal firing and reduction of cognitive impairments. Our results suggest promising potential for the use of RNA re...