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)

AtT-20 cells, which were derived from a murine pituitary tumor and produce ACTH, have until now been considered to originate from pituitary corticotrophs. Here we show that AtT-20 cells constitutively express several neuronal features. First, AtT-20 cells develop cytoplasmic processes whose fine structure is essentially identical to that of neurites and neuronal growth cones. These growth cones (i) are characterized by an extensive membranous reticulum which is derived from the endoplasmic reticulum (ER) since it contains immunoglobulin heavy chain binding protein, protein disulfide isomerase and glucose-6-phosphatase; (ii) are a major site of endocytosis; (iii) form cell-to-cell contacts resembling immature synapses. Second, AtT-20 cells, in contrast to pituitary corticotrophs, contain neurofilaments and express all three neurofilament polypeptides. They also contain the high molecular weight form of microtubule-associated protein 2 and tau protein. Third, AtT-20 cells express the neuron-specific phosphoprotein synapsin I which accumulates in the growth cones prior to contacts forming between growth cones and cells. Our results show that AtT-20 cells exhibit several properties of peptidergic neuronal cells and that the constitutive expression of a variety of these properties is compatible with continuous cell division.
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PMID:Morphological and biochemical evidence showing neuronal properties in AtT-20 cells and their growth cones. 250 49

Alz-50 is a monoclonal antibody raised against ventral forebrain tissue from patients with Alzheimer's disease (AD). It was originally believed that the antigen recognized by Alz-50 was only found in degenerating neurons. However, recent studies indicate that Alz-50 stains neurons in a limited but specific distribution in normal brains throughout life. As the antigen recognized by Alz-50 in normal brains may give some insight into the AD degenerative process, we characterized Alz-50 staining in the normal ovine striatum using immunoblots and immunocytochemistry at the light and electron microscope levels. We then compared the Alz-50 staining pattern with those of NADPH diaphorase histochemistry and immunocytochemistry using antisera against several neuropeptides, Alzheimer-related proteins, and heat-shock proteins. Western blot analysis indicated that the epitope recognized by Alz-50 in the normal sheep brain is on the microtubule-associated protein tau, and preadsorbing Alz-50 with a peptide corresponding to the amino terminus of the tau molecule eliminated staining. Alz-50 labeled a single population of cells in the ovine striatum, the medium aspiny neurons. At the light microscope level, the granular staining pattern closely resembled Alz-50 immunoreactive neurons in the normal human striatum and in cells undergoing early degeneration in AD. Alz-50 immunoreactive neurons stained immunocytochemically with antisera against somatostatin, neuropeptide Y, and histochemically for NADPH diaphorase. These cells were morphologically characterized by smooth dendrites, elaborate local axonal plexuses, and indented nuclei with filamentous inclusions. Ultrastructurally, Alz-50 immunodecorated ribosomes and membranous structures (e.g. vesicles, endoplasmic reticulum), and many boutons which contained Alz-50-positive synaptic vesicles. None of the antisera against other Alzheimer-related proteins, including paired helical filament protein, ubiquitin, beta-amyloid protein, or heat-shock proteins specifically stained the population of cells labelled by Alz-50. Other tau antisera also did not specifically stain these cells. We conclude that Alz-50 recognizes an amino terminal epitope that is exposed on tau proteins within a single, discrete population of neurons in the normal sheep striatum. The presence of this epitope in a normal cell population raises the possibility that the early stages of AD degeneration may involve the activation of a normal cellular pathway that modifies the tau molecule.
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PMID:Alz-50 immunohistochemistry in the normal sheep striatum: a light and electron microscope study. 809 42

Bovine brain tau protein was tagged with the fluorescent dye 5 (and 6)-carboxyx-rhodamine-succinimidyl ester and the functional properties of the fluorescent analog were tested in vitro by kinetic measurement and SDS gel electrophoresis. X-rhodamine tau was competent to bind to microtubules and promote microtubule assembly in vitro. Labeled tau was further characterized by microinjection of cultured Chinese hamster ovary (CHO) cells to study its intracellular distribution and potential new functions. X-rhodamine tau incorporated rapidly into centrosomes within seconds after microinjection. It distinctly labeled the microtubule network as early as 5 to 10 minutes following miroinjection. In addition, X-rhodamine tau was transported into the nucleus and labeled the nucleolus specifically. Double labeling of the injected cells with DiC6(3) indicated that in some cases, fluorescent tau may associate with the endoplasmic reticulum. The concentrations of injected X-rhodamine tau ranged from 1.7 to 5.0 mg/ml, yet distinct bundling of microtubules was not observed. Studies of nocodazole effects on the microtubules established that X-rhodamine tau stabilized microtubules against depolymerization conditions. We conclude that this fluorescent analog of tau is associated with microtubules, the nucleolus, and other microtubule-related structures in living cells, and is competent to stabilize microtubules against microtubule depolymerizing drug treatment. This approach provides a useful model system for the study of modified tau in neurodegenerative disease.
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PMID:Characterization of fluorescently derivatized bovine tau protein and its localization and functions in cultured Chinese hamster ovary cells. 832 32

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.
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PMID:A protein kinase, PKN, accumulates in Alzheimer neurofibrillary tangles and associated endoplasmic reticulum-derived vesicles and phosphorylates tau protein. 973 60

The neuronal microtubule-associated protein tau plays an important role in establishing cell polarity by stabilizing axonal microtubules that serve as tracks for motor-protein-driven transport processes. To investigate the role of tau in intracellular transport, we studied the effects of tau expression in stably transfected CHO cells and differentiated neuroblastoma N2a cells. Tau causes a change in cell shape, retards cell growth, and dramatically alters the distribution of various organelles, known to be transported via microtubule-dependent motor proteins. Mitochondria fail to be transported to peripheral cell compartments and cluster in the vicinity of the microtubule-organizing center. The endoplasmic reticulum becomes less dense and no longer extends to the cell periphery. In differentiated N2a cells, the overexpression of tau leads to the disappearance of mitochondria from the neurites. These effects are caused by tau's binding to microtubules and slowing down intracellular transport by preferential impairment of plus-end-directed transport mediated by kinesin-like motor proteins. Since in Alzheimer's disease tau protein is elevated and mislocalized, these observations point to a possible cause for the gradual degeneration of neurons.
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PMID:Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. 981 97

The clinical symptoms of all forms of Alzheimer's disease (AD) result from a slowly progressive neurodegeneration that is associated with the excessive deposition of beta-amyloid (A beta) in plaques and in the cerebrovasculature, and the formation of intraneuronal neurofibrillary tangles, which are composed primarily of abnormally hyperphosphorylated tau protein. The sequence of cellular events that cause this pathology and neurodegeneration is unknown. It is, however, most probably linked to neuronal signal transduction systems that become misregulated in the brains of certain individuals, causing excessive A beta to be formed and/or deposited, tau to become aggregated and hyperphosphorylated and neurons to degenerate. We hypothesize that a progressive alteration in the ability of neurons to regulate intracellular calcium, particularly at the level of the endoplasmic reticulum, is a crucial signal transduction event that is linked strongly to the initiation and development of AD pathology. In this chapter we will discuss the key findings that lend support to this hypothesis.
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PMID:Dysfunctional intracellular calcium homoeostasis: a central cause of neurodegeneration in Alzheimer's disease. 1144 34

Alzheimer disease is not a single disorder. Etiologically, two different types or even diseases exist: inheritance in 5% to 10% of all Alzheimer cases versus 90% to 95% AD cases whith sporadic origin (SAD). Different susceptibility genes along with adult lifestyle risk-factors- in the case of SAD the risk factor aging- may be assumed to cause the latter disorder. There is evidence that a disturbance in the insulin signal transduction pathway may be a central and early pathophysiologic event in SAD. Both, hypercortisolemia and increased adrenergic activity, in both old age and SAD may render the function of the neuronal insulin receptor vulnerable resulting in a diminished production of ATP. The reduced availability of ATP may damage the function of the endoplasmic reticulum/Golgi apparatus/trans Golgi network generating misfolded and malfolded proteins retained in the cell. In SAD, amyloid precursor protein is found to accumulate intracellularly thus not representing the cause but a driving force in the pathogenesis of SAD. Additionally, both disturbed insulin signaling and reduced ATP forward the hyperphosphorylation of tau protein. Thus, abnormalities in oxidative brain metabolism lead to the formation of two main morphologic hallmarks of SAD: senile plaques and neurofibrillary tangles. Therefore, the therapeutic goal in SAD should be the improvement of the neuronal energy state. Findings from both basic and clinical studies showed that Ginkgo biloba extract (EGb 761) may be appropiate to approach that goal.
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PMID:Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease: therapeutic implications. 1497 12

Early onset generalized dystonia is a severe form of primary dystonia linked to a mutation of the DYT1(TOR1A) gene on chromosome 9q34. DYT1 gene codifies for human torsinA, an AAA+ ATPase associated with the membranes of endoplasmic reticulum (ER) and the synaptic vesicles and proposed to be involved in trafficking of tubular-vesicular membrane through neuronal processes. In this study, the presence and the intracellular distribution of torsinA protein in SH-SY5Y neuroblastoma cells were evaluated by immunofluorescence and Western blot analysis following differentiation with retinoic acid and BDNF. Protein expression was then inhibited by transient antisense transfection and the possible effect on neurite outgrowth was observed. In SH-SY5Y cells torsinA, with an apparent MW of 38 kDa, is endogenously present and distributed, with a punctate pattern, in the cytosol and along the neurites. The protein showed high intensity of immunoreactivity in the neurite varicosities and was partially co-localized with vesicles markers. Terminally differentiated cells showed an increase of protein expression. Oligonucleotide antisense treatment induced a significant response to differentiating stimuli, lead to sprouting of longer neurites and increase in growth cone areas. A relationship between torsinA and tau protein, which is involved in axon elongation and establishment of neuronal polarity, was demonstrated by co-immunoprecipitation experiments. These findings suggest that torsinA, throughout the interaction with microtubule associated proteins, may contribute to control neurite outgrowth and could be involved in maintaining cell polarity.
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PMID:TorsinA negatively controls neurite outgrowth of SH-SY5Y human neuronal cell line. 1515 63

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival agent for neurons, however, its effect on A beta-evoked neuronal death has not been examined. We show that the injection of A beta into New Zealand white rabbit brain activates the endoplasmic reticulum (ER) chaperones, grp 78 and grp 94, and the transcription factor, gadd 153. These effects correlate with the activation of JNK and ERK as well as of microglia and with the phosphorylation of tau protein. Treatment with GDNF inhibits the activation of gadd 153, reduces the phosphorylation of JNK, abolishes the phosphorylation of ERK, prevents microglial activation, greatly reduces apoptotic cells, and does not affect the phosphorylation of tau. Our data suggest that the tau hyperphosphorylation and apoptosis triggered by A beta are two independent events, and that the neuroprotective effect of GDNF against A beta may result either directly by the inhibition of ER stress or indirectly through the inhibition of JNK and ERK activation.
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PMID:GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases. 1519 98

Increased levels of mitochondrial-free calcium have been associated with several cell-death paradigms, such as excitotoxicity and ceramide-mediated neuronal death. In the latter, calcium is transferred from the endoplasmic reticulum to mitochondria by a mechanism that is only partly understood. We show here that CDK5 (cyclin-dependent kinase 5) plays a role. Free calcium levels in the endoplasmic reticulum and mitochondria were measured with fluorescent markers in C2-ceramide-treated primary cultures of mesencephalic neurons and differentiated pheochromocytoma PC12 cells. Calcium levels decreased in the endoplasmic reticulum as they increased in mitochondria. Both changes were blocked by the pharmacological and molecular CDK5 inhibitors roscovitine and a dominant-negative form of CDK5. Although the kinase did not mediate the transfer of calcium per se, which required the proapoptotic Bcl-2 family protein t-Bid (the truncated form of Bid), it facilitated the transfer by inducing the clustering of endoplasmic reticulum and mitochondria around the centrosome where they formed close contacts, as shown by immunocytochemistry and electron microscopy. Organelle clustering resulted from CDK5-dependent phosphorylation of the microtubule-associated protein tau on threonine 231. This caused its release from microtubules into the soluble fraction of cellular proteins, which appears to favor retrograde transport of the organelles. Mutation of threonine 231 to alanine, so that tau could not be phosphorylated at this site, prevented the ceramide-induced release of tau from microtubules, organelle clustering, the increase in mitochondrial-free calcium levels, and neuronal death, demonstrating the importance of the CDK5-dependent signaling cascade in this calcium-dependent cell-death mechanism.
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PMID:Neurotoxic calcium transfer from endoplasmic reticulum to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau. 1584 19


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