Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The paired helical filaments (PHFs) found in Alzheimer's disease (AD) brains are composed primarily of the microtubule-associated protein tau. PHF-tau is in a hyperphosphorylated state and is unable to promote microtubule assembly. We investigated whether the inhibition of tau binding to microtubules is increased when tau is phosphorylated by different kinases in combination with GSK-3. We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. From these observations we estimate that the phosphorylation of Thr 231, Ser 235, and Ser 262 contributes approximately 26, approximately 9, and approximately 33%, respectively, of the overall inhibition of tau binding to microtubules. Together, our results indicate that the binding of tau to microtubules is controlled by the phosphorylation of several sites, among which are Thr 231, Ser 235, and Ser 262.
Arch Biochem Biophys 1998 Sep 15
PMID:Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. 973 71

A possible role for a protein kinase, PKN, a fatty acid-activated serine/threonine kinase with a catalytic domain homologous to the protein kinase C family and a direct target for Rho, was investigated in the pathology of Alzheimer's disease (AD) using a sensitive immunocytochemistry on postmortem human brain tissues and a kinase assay for human tau protein. The present study provides evidences by light, electron, and confocal laser microscopy that in control human brains, PKN is enriched in neurons, where the kinase is concentrated in a subset of endoplasmic reticulum (ER) and ER-derived vesicles localized to the apical compartment of juxtanuclear cytoplasm, as well as late endosomes, multivesicular bodies, Golgi bodies, secretary vesicles, and nuclei. In AD-affected neurons, PKN was redistributed to the cortical cytoplasm and neurites and was closely associated with neurofibrillary tangles (NFTs) and their major constituent, abnormally modified tau. PKN was also found in degenerative neurites within senile plaques. In addition, we report that human tau protein is directly phosphorylated by PKN both in vitro and in vivo. Thus, our results suggest a specific role for PKN in NFT formation and neurodegeneration in AD damaged neurons.
J Neurosci 1998 Sep 15
PMID:A protein kinase, PKN, accumulates in Alzheimer neurofibrillary tangles and associated endoplasmic reticulum-derived vesicles and phosphorylates tau protein. 973 60

Argyrophilic grain disease (AGD) is a distinct degenerative disorder of the human brain associated with the formation of abnormally phosphorylated tau protein. AGD-related cytoskeletal changes are known to affect specific subsets of nerve cells and oligodendrocytes. Here we demonstrate a remarkable association between the apolipoprotein E (ApoE) epsilon2 allele and AGD. Individuals afflicted with AGD (n = 48) reveal a significantly higher frequency of the epsilon2 allele compared with controls (n = 43) (22% versus 4%, P < 0.0002). The association between AGD and epsilon2 allele of ApoE suggests that AGD can be distinguished from other neurodegenerative disorders not only neuropathologically, but also genetically.
Acta Neuropathol 1998 Sep
PMID:Argyrophilic grain disease is associated with apolipoprotein E epsilon 2 allele. 975 52

alpha-Synuclein has been implicated in the pathogenesis of several neurodegenerative disorders based on the direct linking of missense mutations in alpha-synuclein to autosomal dominant Parkinson's disease and its presence in Lewy-like lesions. To gain insight into alpha-synuclein functions, we have investigated whether it binds neuronal proteins and modulates their functional state. The microtubule-associated protein tau was identified as a ligand by alpha-synuclein affinity chromatography of human brain cytosol. Direct binding assays using (125)I-labeled human tau40 demonstrated a reversible binding with a IC(50) about 50 pM. The interacting domains were localized to the C terminus of alpha-synuclein and the microtubule binding region of tau as determined by protein fragmentation and the use of recombinant peptides. High concentrations of tubulin inhibited the binding between tau and alpha-synuclein. Functionally, alpha-synuclein stimulated the protein kinase A-catalyzed phosphorylation of tau serine residues 262 and 356 as determined using a phospho-epitope-specific antibody. We propose that alpha-synuclein modulates the phosphorylation of soluble axonal tau and thereby indirectly affects the stability of axonal microtubules.
J Biol Chem 1999 Sep 03
PMID:alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. 1046 79

Perturbations in the microtubule-associated protein tau occur in several human neurodegenerative diseases. In Alzheimer's disease and progressive supranuclear palsy (PSP), tau proteins assemble into straight and paired helical filaments that form intraneuronal deposits of neurofibrillary tangles (NFTs). The mechanisms underlying the aberrant assembly of tau into NFTs is unknown. To determine whether alterations in the expression of the carboxyl-terminal variants of tau contribute to NFT formation, we analyzed tau mRNA isoform expression in select regions of control, Alzheimer's disease, and PSP brains. In Alzheimer's disease, there were no alterations in tau mRNA isoform expression. However, in PSP, the levels of tau mRNA isoforms containing four microtubule binding domains were increased in the brainstem but not the frontal cortex or cerebellum. The brainstem in PSP has extensive NFT pathology, whereas the frontal cortex and cerebellum are relatively spared, suggesting that alterations in tau mRNA isoform expression occur in NFT-vulnerable regions in this disease. An increase in the four-repeat tau mRNA may lead to an increase in four-repeat tau protein isoforms and may contribute to the formation of NFTs in PSP. A similar increase in four-repeat tau mRNA has been reported for mutations associated with frontotemporal dementia and parkinsonism linked to chromosome 17.
Ann Neurol 1999 Sep
PMID:Overexpression of four-repeat tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer's disease. 1048 63

Argyrophilic grain disease (AgD), a frequent type of late onset dementia, is characterized by the occurrence of Gallyas-stained neuropil grains in the hippocampus, entorhinal cortex, amygdala and hypothalamus. High numbers of neurons containing hyperphosphorylated tau protein, but devoid of tangles, are encountered in areas rich in argyrophilic grains (ArGs). A third type of change consists of slender argyrophilic and tau-immunoreactive cytoplasmic inclusions in white matter oligodendrocytes, the coiled bodies. We now extend earlier studies on glial pathology in AgD (20 cases) and compare the results with glial changes in old age (10 cases) and Alzheimer's disease (AD; 7 cases). Numerous non-argyrophilic, non-neuronal tau-positive stellate cells in the amygdala and anterior entorhinal cortex were consistently found in all of the 20 AgD cases but not in AD cases. Double-labelling experiments performed on paraffin sections with phosphorylation-dependent anti-tau antibody AT8, anti-glial fibrillary acidic protein and anti-CD44, revealed coexpression of these markers in stellate cells. The high expression of CD44 indicate that they probably correspond to reactive astrocytes. Unlike astrocytic plaques in corticobasal degeneration (CBD), where AT8 reactivity is accumulating in distal astrocytic processes, tau reactivity in AgD was found in all astrocytic cell compartments. The absence of glial fibrillary tangles further distinguished tau-labelled astrocytes in AgD from astrocytic plaques in CBD and tufted astrocytes in progressive supranuclear palsy (PSP). In contrast to AD and aged non-demented control cases tau-positive non-argyrophilic astrocytes represent a consistent finding in anterior limbic structures in AgD. Our findings point to a more widespread pathology of the glial cell population in AgD than previously supposed, and will be of further help in differentiating AgD from other neurodegenerative disorders, including AD, PSP, CBD and Pick's disease.
Acta Neuropathol 1999 Sep
PMID:Astrocytes expressing hyperphosphorylated tau protein without glial fibrillary tangles in argyrophilic grain disease. 1048 82

Pick's disease chiefly is characterized by progressive degeneration of specific telencephalic cortical areas and associated subcortical nuclei. Components of the cerebellum also are affected. Immunoreactions for abnormally hyperphosphorylated tau protein, indicating the development of cytoskeletal anomalies in a few susceptible neuroectodermal cell types, permit visualization and identification of the pathology. Initially, accumulations of nonargyrophilic material appear in the perikarya and cellular processes of susceptible nerve cells. In some neuronal types, the abnormal deposits are transformed into more condensed inclusions, so-called Pick bodies in perikarya and Pick neurites in cellular processes, some of which become argyrophilic in the course of the disease. This study employs silver techniques and immunoreactions to draw attention to Pick's disease-associated lesions in the cerebellar cortex and cerebellar nuclei. Immunoreactive rosettes, which correspond to the terminal synaptic boutons of mossy fibers, frequently are encountered in the cerebellar granule cell layer. Some cases of Pick's disease also exhibit afflicted monodendritic brush cells in this layer. Single immunopositive Purkinje cells occasionally are seen as well. The brunt of the alterations is borne by cerebellar subdivisions receiving dense input from the telencephalic cortex through the pontocerebellar pathway (neocerebellum). The dentate nucleus shows immunoreactive axons with numerous varicose thickenings which remain confined to the reaches of this band-like nuclear gray and probably represent collaterals of altered mossy fibers. A large number of the dentate projection cells also contain the abnormal material in the perikarya, as well as in all of the neuronal processes. Many of these cells develop spherical nonargyrophilic condensations of this material. Output of the neocerebellum is conveyed to extended territories of the telencephalic cortex via the dentate nucleus and thalamus. Therefore, all of the cerebellar territories which receive major input from and generate output chiefly to the telencephalic cortex (pontocerebellum or neocerebellum) are notably afflicted in Pick's disease. Other subdivisions with preponderant input from the spinal cord and/or other noncortical sources remain intact or else are only minimally involved. It is concluded that the pattern of cerebellar involvement reflects Pick's disease-associated neocortical destruction.
Exp Neurol 1999 Sep
PMID:Cerebellar involvement in Pick's disease: affliction of mossy fibers, monodendritic brush cells, and dentate projection neurons. 1048 84

Glycogen synthase kinase 3beta (GSK-3beta) is a proline-directed kinase that forms part of the wingless signaling pathway. Recent studies have shown that GSK-3beta phosphorylates the microtubule-associated protein tau in vitro and in cell culture. Tau is the principal component of the paired helical filaments (PHFs) found in the brains of patients with Alzheimer disease, and PHF-tau is hyperphosphorylated. GSK-3beta is therefore one of the candidate kinases for phosphorylating tau in Alzheimer disease. GSK-3beta activity is negatively regulated by phosphorylation on serine 9 and positively regulated by phosphorylation on tyrosine 216. However, since overexpression of GSK-3beta by transfection leads to increased activity in the absence of any stimuli, GSK-3beta activity may also be regulated at the transcriptional level. Indeed, increased GSK-3beta protein levels are found in Alzheimer disease brains, and GSK-3beta is found associated with PHFs in Alzheimer disease. To understand how GSK-3beta activity may be regulated at the transcriptional level, we have isolated the human GSK-3beta promoter. The GSK-3beta promoter does not contain a conventional TATA box although several other transcription factor binding sites were identified. A putative transcription start site was mapped by 5' RACE. Transfection of various GSK-3beta promoter CAT reporter genes into both COS-7 cells and SHSY5Y neuronal cells revealed that the GSK-3beta promoter is more active in neuronal cells. Such transfection studies involving promoter deletion mutants revealed that a negative transcriptional response element may be present at position -1421 to -1363 and an activator sequence at position -427 to -384. CP2 binding sites were also present within the promoter. CP2 has recently been shown to interact with the Alzheimer disease amyloid precursor protein binding protein Fe65. The significance of these results with respect to Alzheimer disease pathogenesis are discussed.
Genomics 1999 Sep 01
PMID:Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter. 1048 3

A number of related conditions, including progressive supranuclear palsy (PSP), corticobasal degeneration, Pick's disease, and the parkinsonism dementia complex of Guam, are characterized by the deposition of tau neurofibrillary tangles in the absence of amyloid pathology. These diseases share some overlap in their topography and clinical features but can be subdivided into three main groups according to the isoforms of the alternatively spliced tau gene that are deposited. The recent description of mutation in tau in frontotemporal dementia, and a common variant of tau that predisposes to PSP, and the relationship of these changes to the tau protein subgroups offers new insights into the pathogenesis of these disorders.
Mov Disord 1999 Sep
PMID:Neurofibrillary tangle parkinsonian disorders--tau pathology and tau genetics. 1049 33

Accumulation of paired helical filaments (PHFs) in neurofibrillary tangles, neuropil threads, and dystrophic neurites is one of the major neuropathological hallmarks of Alzheimer disease (AD). The principal protein subunit of PHFs is the abnormally hyperphosphorylated tau. Glycogen synthase kinase 3beta (GSK-3beta) is one of the candidate kinases involved in PHF-tau formation. To play a role in PHF-tau formation, it would be expected that GSK-3beta is active in tangle bearing neurons. In the present study, we investigated the regional and intracellular distributions of active and inactive forms of GSK-3beta in brains staged for neurofibrillary changes. We found that neurons with tangle-like inclusions positive for active, but not inactive, GSK-3beta appear initially in the Pre-alpha layer of the entorhinal cortex and extend to other brain regions, coincident with the sequence of the development of neurofibrillary changes. Active, but not inactive, GSK-3beta was found to initially accumulate in the cytoplasm of pretangle neurons. These data provide direct in situ evidence that is consistent with the involvement of GSK-3beta in PHF-tau formation.
J Neuropathol Exp Neurol 1999 Sep
PMID:Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. 1049 43


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