Alternative Splicing of Amino-Terminal Tau mRNA in Rat Spinal Cord during Development and Following Axonal Injury (original) (raw)

Tau mRNA isoforms following sciatic nerve axotomy with and without regeneration

Molecular Brain Research, 1997

The microtubule-associated protein tau promotes the polymerization and stabilization of microtubules in normal neurons and is the Ž . main component of paired helical filaments, one of the pathological structures characteristic of Alzheimer's disease AD . In adult Ž . neurons alternative splicing generates tau isoforms with 4 microtubule binding domains 4R tau while tau in developing neurons contains Ž . only 3 such domains 3R tau . The extra microtubule binding domain confers adult tau with an increased ability to interact with and stabilize microtubules. We hypothesized that tau gene expression would revert to the developmental pattern following nerve injury. The sciatic nerve of adult rats was unilaterally crushed or transected and tau mRNA isoform expression in the spinal cord was examined by reverse transcriptase-polymerase chain reaction. At 2 and 3 days post-crush, both the 3R and 4R tau mRNA isoform levels on the injured side had decreased compared to the contralateral side. However, the ratio of 4R to 3R tau mRNA was not significantly different between the two sides at any post-crush time point examined. Following nerve transection, a significant increase in the 3R tau mRNA isoform on the transected compared to the contralateral side occurred at 14 days; the ratio of 4R to 3R tau mRNA was significantly decreased on the transected compared to the contralateral side at 7, 14 and 42 days. These results suggest that a recapitulation of the developmental pattern of 3R tau gene expression occurs following nerve transection but not nerve crush. Our results combined with the recent findings that the 3R tau protein isoform preferentially forms paired helical filament-like structures in vitro suggests that an increased expression of the 3R tau mRNA isoform may also occur in AD. q 1997 Elsevier Science B.V.

Prominent Axonopathy in the Brain and Spinal Cord of Transgenic Mice Overexpressing Four-Repeat Human tau Protein

American Journal of Pathology, 1999

Mutations in the human tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Some mutations , including mutations in intron 10 , induce increased levels of the functionally normal four-repeat tau protein isoform , leading to neurodegeneration. We generated transgenic mice that overexpress the four-repeat human tau protein isoform specifically in neurons. The transgenic mice developed axonal degeneration in brain and spinal cord. In the model , axonal dilations with accumulation of neurofilaments , mitochondria , and vesicles were documented. The axonopathy and the accompanying dysfunctional sensorimotor capacities were transgene-dosage related. These findings proved that merely increasing the concentration of the four-repeat tau protein isoform is sufficient to injure neurons in the central nervous system , without formation of intraneuronal neurofibrillary tangles. Evidence for astrogliosis and ubiquitination of accumulated proteins in the dilated part of the axon supported this conclusion. This transgenic model , overexpressing the longest isoform of human tau protein, recapitulates features of known neurodegenerative diseases , including Alzheimer's disease and other tauopathies. The model makes it possible to study the interaction with additional factors , to be incorpo-rated genetically, or with other biological triggers that are implicated in neurodegeneration.

Tau protein isoforms, phosphorylation and role in neurodegenerative disorders11These authors contributed equally to this work

Brain Research Reviews, 2000

Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Microtubules are involved in maintaining the cell shape and serve as tracks for axonal transport. Tau proteins also establish some links between microtubules and other cytoskeletal elements or proteins. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of intraneuronal and glial fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, a direct correlation has been established between the progressive involvement of the neocortical areas and the increasing severity of dementia, suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. The recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies.

Expression patterns of tau mRNA isoforms correlate with susceptible lesions in progressive supranuclear palsy and corticobasal degeneration

Molecular Brain Research, 2002

Deposition of hyperphosphorylated tau (p-tau) has been observed in several neurodegenerative diseases. The six isoforms of tau are divided into two main groups including three repeat (3R) and four repeat (4R) microtubule-binding domains. Using quantitative RT-PCR method and immunohistochemistry with phosphorylation dependent anti-tau antibody (AT8), we investigated the expression level of tau mRNA isoforms in the frontal cortex and globus pallidus of patients with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) to determine whether altered expression patterns of tau mRNA isoforms correlate with p-tau accumulation. The 4R / 3R ratios in frontal cortices of CBD and globus pallidus of PSP and CBD were significantly higher than the control (P,0.05). There was no correlation between the expression patterns of tau mRNA isoforms and p-tau accumulation. Our findings suggest that neurodegeneration of PSP and CBD could be regulated by alternative splicing of tau mRNA to yield high 4R / 3R ratio. In addition, the lack of correlation between the expression pattern of tau mRNA isoforms and p-tau accumulation suggests that not only alternative splicing of tau mRNA, but also other factors such as post-transcriptional or translational modifications may play a role in the pathogenesis of specific neurodegeneration in PSP and CBD.

Phosphorylation of specific sets of tau isoforms reflects different neurofibrillary degeneration processes

FEBS Letters, 1998

Tau proteins are the basic components of filaments that accumulate within neurons during neurofibrillary degeneration, a degenerating process with disease-specific phenotypes. This specificity is likely to be sustained by both phosphorylation state and isoform content of tau aggregates that form neuronal inclusions. In the present study, characterization of tau isoforms involved in neurofibrillary degeneration in Alzheimer's disease, Pick's disease, corticobasal degeneration and progressive supranuclear palsy was performed. Both analyses by immunoblotting using specific tau antibodies and cell transfection by tau isoform cDNAs allowed us to demonstrate the aggregation of (1) the six hyperphosphorylated tau isoforms in Alzheimer's disease, (2) tau isoforms without exon 10-encoding sequence in Pick's disease and (3) hyperphosphorylated exon 10-tau isoforms in corticobasal degeneration and progressive supranuclear palsy. Thus, neurofibrillary degeneration phenotypes are likely to be related to the phosphorylation of different combinations of tau isoforms (with and/or without exon 10-encoding sequence) in subpopulations of neurons.

Tau protein in neurodegenerative diseases - a review

2017

The study of rare, inherited forms of different diseases resulted in the discovery of gene defects that cause inherited variants of the respective diseases. The defective genes were found to encode major molecular players leading to the neuropathological lesions or factors that characterize these diseases. The exact role of the tau protein in the neurodegenerative process is still under debate. It is very important to understand the normal biological roles of tau and the specific events that induce tau to become neurotoxic. Tau is the major microtubule-associated protein (MAP) of a mature neuron. The other neuronal MAPs are MAP1 and MAP2. These three MAPs perform similar function, promoting assembly and stability of microtubules. Tau protein was isolated as a microtubule-associated factor in the porcine brain. It was isolated as a protein that co-purified with tubulin and had the ability to promote microtubule assembly in vitro. Normal adult human brain tau contains 2-3 moles phosph...

Loss of tau elicits axonal degeneration in a mouse model of Alzheimer's disease

Neuroscience, 2010

A central issue in the pathogenesis of tauopathy is the question of how tau protein dysfunction leads to neurodegeneration. We have previously demonstrated that the absence of tau protein is associated with destabilization of microtubules and impaired neurite outgrowth . We now hypothesize that the absence of functional tau protein may render the central nervous system more vulnerable to secondary insults such as the overexpression of mutated beta amyloid precursor protein (APP) and traumatic brain injury. We therefore crossed tau knockout mice to mice overexpressing a mutated human APP (APP 670,671 , A sw ) and created a mouse model (A sw /mTau −/− ) that provides evidence that the loss of tau causes degeneration of neuronal processes. The overexpression of APP 670,671 in tau knockout mice, elicits the extensive formation of axonal spheroids. While spheroids are only found associated with Aβ plaques in mice expressing APP 670,671 on an endogenous mouse tau background , A sw /mTau −/− mice have spheroids not only surrounding Aβ plaques but also in white matter tracts and in the neuropil. Plaque associated and neuropil dystrophic neurites and spheroids are prominent features of Alzheimer's disease . Thus our current data suggests that loss of tau may lead to neurodegeneration.

Modulation of Tau Isoforms Imbalance Precludes Tau Pathology and Cognitive Decline in a Mouse Model of Tauopathy

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...

Investigation of the role of tau gene transcriptional regulation in neurodegeneration

Alzheimer's & Dementia, 2011

Although the tau gene (MAPT) is not mutated in the majority of tauopathies, there are pathological disturbances in tau-isoform homeostasis. Investigation into MAPT linkage disequilibrium and haplotype structure, and the common variation of MAPT associated with increased risk of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) identified a possible basis for the disturbances in tau-isoform homeostasis. Of multiple haplotypes in the H1 clade, the H1c sub-haplotype drives the association with PSP and CBD, suggesting that it carries the pathogenic variation leading to increased risk of these largely sporadic disorders. The aim of this project was to investigate the regulation of the transcription of MAPT by first identifying transcription factors (TFs) and TF complexes that bind to the MAPT core promoter and its conserved regulatory domains. The specific aim was to determine if differential binding of TFs and TF complexes to the allelic variants of the SNPs in the MAPT promoter region forms the basis of the allele-specific differences in MAPT transcription and splicing that we have observed in vitro and in vivo. Results from electrophoretic mobility shift assays, pull-down experiments and mass spectrometry had shown potentially novel proteins binding to the disease-associated SNP under investigation. Bioinformatic analyses helped to stratify these proteins according to possible relevance. While immunoblotting alongside co-transfection of siRNA and luciferase promoter construct experiments had shown initial evidence of a complicated relationship between cis and trans factors within the tau promoter region. These findings were novel and they provide new insight into the regulation of one of the most important genes in neurodegeneration. The identification of MAPT transcriptional machinery would provide further insight into the role of MAPT in neurodegeneration and the basis for therapeutic intervention.

Allen, B, Ingram, E, Takao, M, Smith, MJ, Jakes, R, Virdee, K et al.. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22: 9340-9351

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

The identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic mutations in transgenic animals. Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation. At 5-6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis. According to light microscopy, many nerve cells in brain and spinal cord were strongly immunoreactive for hyperphosphorylated tau. According to electron microscopy, abundant filaments made of hyperphosphorylated tau protein were present. The majority of filaments resembled the half-twisted ribbons described previously in cases of FTDP-17, with a minority of filaments resembling the paired helical filaments of Alzheimer's disease. Sarkosyl-insoluble tau from brains and spinal cords of transgenic mice ran as a hyperphosphorylated 64 kDa band, the same apparent molecular mass as that of the 383 aa tau isoform in the human tauopathies. Perchloric acidsoluble tau was also phosphorylated at many sites, with the notable exception of serine 214. In the spinal cord, neurodegeneration was present, as indicated by a 49% reduction in the number of motor neurons. No evidence for apoptosis was obtained, despite the extensive colocalization of hyperphosphorylated tau protein with activated MAP kinase family members. The latter may be involved in the hyperphosphorylation of tau.