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

At autopsy, a most distinctive pathology seen in Alzheimer's disease (AD) brains is numerous abnormal neurons filled with neurofibrillary tangles (NFTs) containing stable complexes of hyperphosphorylated tau (PHF), neurofilaments and various kinases, among other proteins. Though these neuronal aggregates have been actively studied, their nature and origin are still poorly understood. Our studies of regulation of phosphorylation in neurons of the squid giant fiber system, using P13(suc1) affinity chromatography, suggest that neuronal phosphorylation of cytoskeletal proteins is compartmentalized into active axonal and inactive cell body-specific multimeric complexes of kinases, substrates and phosphatases. To determine whether such compartment-specific phosphorylation complexes are present in human brains, we separated gray matter (enriched in cell bodies) and white matter (enriched in axons) from normal and AD brains and studied the total kinase activities in lysates, pellets and P13(suc1) complexes. In addition, Western blot analysis was used to characterize the proteins associated with P13(suc1) multimeric complexes extracted from gray and white matter. We tested the hypothesis that P13 phosphorylation complexes were abnormally compartmentalized in AD neurons with the more active complexes shifted to cell bodies (gray matter) instead of axons (white matter). We found that (1) endogenous and exogenous substrate-dependent kinase activities of AD and control brain extracts were similar in both gray and white matter. (2) Long post mortem times tend to erase any differences in kinase activity between control and AD extracts. In contrast to shorter post mortem times (4.5-10 hrs), long post mortem times (13-34 hrs) significantly minimize the variances in kinase activities between control and AD brain extracts suggesting that cell death and proteolysis may eliminate any intrinsic differences in enzyme activities. (3) Except for the significantly higher level of histone phosphorylation in control white extracts, the kinase activities of P13(suc1)-derived multimeric complexes from gray and white matter were also similar in control and AD brains. Here, too, variances between control and AD distributions were significantly different (p < 0.001-0.02) suggesting that the P13 complexes were different. We also found differences in the Western blot profiles of P13suc1-associated kinases and cytoskeletal proteins; higher expression of phosphorylated NF-H and PHF-tau in gray matter of AD brains was detected. We believe that such differences in P13 complexes from human control and AD brain samples displaying extensive heterogeneity in age, post mortem time and clinical history, may be important.
 ...
PMID:Topographic regulation of kinase activity in Alzheimer's disease brains. 1244 29

Neurofilaments are neuron-specific intermediate filaments. They are classed into three groups according to their molecular masses: neurofilament heavy, middle and light chains (NF-H, NF-M and NF-L). Neurofilaments assemble and form through the association of their central alpha-helical coiled-coil rod domains. NF-H and NF-M are distinct from NF-L as they contain a carboxyl-terminal tail domain, which appears to form connections with adjacent structures and other neurofilaments. Together with other axonal components such as microtubules, they form the dynamic axonal cytoskeleton. They maintain and regulate neuronal cytoskeletal plasticity through the regulation of neurite outgrowth, axonal caliber and axonal transport. Neurofilaments contain KSP repeats that are consensus motifs for the proline-directed kinases and are extensively phosphorylated in vivo, and their functions are thought to be regulated through their phosphorylation. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed kinase, whose activity is restricted to the neuron through the neuronal-specific distribution of its activators p35 and p39. Cdk5 is the only kinase that affects the electrophoretic mobility of human NF-H and is thought to be the major neurofilament kinase. Cdk5 is involved in crosstalk with other signal transduction pathways such as the mitogen-activated protein kinase and myelin-associated glycoprotein pathways to influence the phosphorylation of neurofilaments and other cytoskeletal proteins. Both the hyperactivation of Cdk5 activity and subsequent hyperphosphorylation of neurofilaments and the microtubule-associated protein tau have been implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis. Here we review the functions of neurofilaments and the significance of Cdk5 phosphorylation of neurofilaments.
 ...
PMID:Cyclin-dependent kinase 5 in neurofilament function and regulation. 1467 12

In our previous study in rats acutely exposed to As, we observed an effect of As on neurofilaments in the sciatic nerve. This study deals with the effects of inorganic As in Wistar rats on the cytoskeletal protein composition of the sciatic nerve after subchronic intoxication. Sodium meta-arsenite (NaAsO2) dissolved in phosphate-buffered saline (PBS) was administered daily in doses of 0, 3 and 10 mg/kg body weight/day (n=9 rats/group) by intragastric route for 4, 8 and 12 week periods. Toxicokinetic measurements revealed a saturation of blood As in the 3- and 10-mg/kg dose groups at approximately 14 microg/ml, with an increase in renal clearance of As at increasing doses. After exsanguination, sciatic nerves were excised and the protein composition was analyzed. Analysis of the sciatic nerves showed compositional changes in their proteins. Protein expression of neurofilament Medium (NF-M) and High (NF-H) was unchanged. Neurofilament protein Low (NF-L) expression was reduced, while mu- and m-calpain protein expression was increased, both in a dose/time pattern. Furthermore, NF-H protein was hypophosphorylated, while NF-L and microtubule-associated protein tau (MAP-tau) proteins were (hyper)-phosphorylated. In conclusion, we show that expression of mu- and m-calpain protein is increased by exposure to As, possibly leading to increased NF-L degradation. In addition, hyperphosphorylation of NF-L and MAP-tau by As also contribute to destabilization and disruption of the cytoskeletal framework, which eventually may lead to axonal degeneration.
 ...
PMID:Arsenic-induced neurotoxicity in relation to toxicokinetics: effects on sciatic nerve proteins. 1867 24

A simple method for differentiating human-derived SH-SY5Y neuroblastoma cells to provide a stable, mature, neuronal morphology is described. SH-SY5Y cells can be induced to differentiate terminally with retinoic acid in medium with low levels of serum. The morphological differentiation of the parental cell line SK-N-SH was compared with that seen in the SH-SY5Y cells. Changes in the cytoskeleton of SH-SY5Y cells indicated that differentiation proceeds continuously over the 1-month period studied after initiating differentiation. Immunoblot analysis demonstrated increased expression of the high molecular weight neurofilament polypeptide NF-H, the microtubule-associated protein tau, and the synaptic vesicle-associated protein synapsin I, indicating that an increasingly mature, neuronal phenotype was being expressed. The cultures were not dependent on retinoic acid for continued survival. SH-SY5Y cultures differentiated over extended periods should provide a good in vitro model for studying the neurotoxic potential of compounds and mechanisms of toxicity, particularly in longer-term or multiple exposure studies, for example on cytoskeletal function, where acute toxicity is not the aspect of interest.
 ...
PMID:Phenotypic morphology and the expression of cytoskeletal markers during long-term differentiation of human SH-SY5Y neuroblastoma cells. 2065 Feb 35

The role of humoral immunity related to neuron- and disease-specific cytoskeletal proteins patients with Alzheimer disease (AD) is unknown. We measured antibodies against tau protein, light and heavy (NFH) neurofilaments using ELISA in 80 paired serum and cerebrospinal fluid (CSF) samples from patients with AD, with other dementias (OD), with neuro-inflammatory diseases (IC) and 25 controls (NC). We estimated intrathecal synthesis according to the formula (CSF/serum anti-neurocytoskeletal IgG)/(CSF/serum total IgG). AD patients had significantly higher intrathecal anti-tau and anti-NFH antibodies than the other groups. These innovative findings may hint at specific alterations in humoral anti-neurocytoskeletal immunity and selectivity in AD, which could have diagnostic and immunotherapeutic implications.
 ...
PMID:Patients with Alzheimer disease have elevated intrathecal synthesis of antibodies against tau protein and heavy neurofilament. 2294 89


<< Previous 1 2