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 solution conformation of tubulin-beta(422-434)-NH2 (YQQYQDATADEQG-NH2) and its Nac-DATADEQG-NH2 fragment has been studied by two-dimensional 1H-nmr spectroscopy in CD3OH/H2O (90/10 v/v) at neutral and low pH. The 13 amino acid peptide is a segment of the C-terminal region of tubulin, and is directly involved in the selective binding site with microtubule-associated proteins MAP-2 and the tau protein. Based on correlated spectroscopy, total correlation spectroscopy, and rotating frame nuclear Overhauser effect spectroscopy experiments, a complete assignment of all proton resonances was achieved, and the conformation of the backbone could be deduced from coupling constants, NH temperature coefficients, and nuclear Overhauser effects. The spectroscopic evidence indicates that the T8-Q12 section of both molecules forms one complete alpha-helical turn, stabilized by a NH (Q12)-C = O (T8) hydrogen bond. Furthermore, strong pH-dependent backfolding of the E11 side chain to its own NH proton was found. In addition, close proximity between the aromatic side chains of Y1, Y4, and the alpha-helical part, resulting in some substantial chemical shift changes when comparing the entire 13-mer with the octamer, could be explained in terms of a nonclassical kink in the DATA section. The conformational space is dominated by extended structures and the nonextended conformers are only a minor, yet spectroscopically clearly discernible entity. The presence of the alpha-helical region at the C-terminus of the 13-mer is important because binding studies of this peptide with MAP-2 indicate that the D10-E11-Q12-G13 fragment is critical for the binding interaction.
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PMID:The solution conformation of tubulin-beta(422-434)-NH2 and its Nac-DATADEQG-NH2 fragment based on NMR. 186 94

In 11 patients with distal myopathy with rimmed vacuole formation (DMRV), a well-known autosomal recessively inherited disorder, the rimmed vacuole formation appears to be the main pathological change accounting for the progressive muscle fiber degeneration. To gain a better understanding of the pathophysiology of the vacuole formation, we applied Congo red and immunohistochemical stains to muscle biopsies from these patients and the results were compared with those of patients with inclusion body myositis (IBM). The vacuoles in DMRV contained Congophilic amyloid material and deposits immunoreactive for beta-amyloid protein, both the NH2 and COOH termini of beta-amyloid protein precursor, ubiquitin, and tau protein. These results were similar to those seen in our present cases of IBM as well as in previously reported cases. Therefore, there may be no pathogenetic differences in the formation of rimmed vacuoles in DMRV and IBM. Nevertheless, the degenerative process involved in rimmed vacuole formation in various diseases may share a common pathogenetic mechanism with that in amyloid-plaque formation in Alzheimer's disease brain as has been proposed previously.
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PMID:Muscle fiber degeneration in distal myopathy with rimmed vacuole formation. 770 28

Synthetic peptide representing the site Ser-41 in vimentin, Leu-Gly-Ser41-Ala42-Leu-Arg44-Arg-Arg-NH2, and its analogs in which Ala-42 was replaced by various amino acids were tested as substrates for cdc2 kinase. Among them, the analog containing sarcosine as well as proline was an excellent substrate. The result suggests that the N-substituted structure of proline immediately following the site is important for cdc2 kinase phosphorylation. Replacement of Ala-42 by polar amino acids, especially lysine, had negative effects on peptide phosphorylation. The peptides in this study were also assayed with another type of proline-directed protein kinase, tau protein kinase II. The substrate specificity differed essentially from that of cdc2 kinase.
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PMID:Phosphorylation of synthetic vimentin peptides by cdc2 kinase. 837 19

Synapses are ultrastructural sites for memory storage in brain, and synaptic damage is the best pathologic correlate of cognitive decline in Alzheimer's disease (AD). Post-translational hyperphosphorylation, enzyme-mediated truncation, conformational modifications, and aggregation of tau protein into neurofibrillary tangles (NFTs) are hallmarks for a heterogeneous group of neurodegenerative disorders, so-called tauopathies. AD is a secondary tauopathy since it is pathologically distinguished by the presence of amyloid-beta (Abeta)-containing senile plaques and the presence of tau-positive NFTs in the neocortex and hippocampus. Here, we report that a 20-22 kDa NH2-truncated tau fragment is largely enriched in human mitochondria from cryopreserved synaptosomes of AD brains and that its amount in terminal fields correlates with the pathological synaptic changes and with the organelle functional impairment. This NH2-truncated tau form is also found in other human, not AD-tauopathies, while its presence in AD patients is linked to Abeta multimeric species and likely to pathology severity. Finally native, patient-derived, Abeta oligomers-enriched extracts likely impair the mitochondrial function by the in vitro production of 20-22 kDa NH2-tau fragments in mature human SY5Y and in rat hippocampal neurons. Thus our findings suggest that the mitochondrial NH2-derived tau peptide distribution may exacerbate the synapse degeneration occurring in tauopathies, including AD, and sustain the in vivo NH-2 tau cleavage inhibitors as an alternative drug discovery strategies for AD therapy.
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PMID:A NH2 tau fragment targets neuronal mitochondria at AD synapses: possible implications for neurodegeneration. 2057 Dec 15

Truncation at N-terminal domain of tau protein is early associated with neurofibrillary pathology in several human tauopathies, including Alzheimer's disease (AD). In affected subjects, the monitoring of total (t-tau) and/or phosphorylated tau (p-tau) levels in cerebrospinal fluid (CSF) provides a reliable, indirect evaluation of cellular changes occurring in vivo and the identification of additional CSF biomarkers would better assist with the clinical practice, allowing a broader profile of underlying ongoing neurodegeneration. Here we show that a 20-22 kDa NH2-truncated form of human tau (i.e., NH2htau), a neurotoxic fragment of the full length protein (htau40) that we previously found in synapses from subjects affected by different tauopathies: (i) is not a normal constituent of CSF, unlike t-tau and p-tau, being exceptionally detected in patients without cognitive impairment; (ii) discriminates, with a weak specificity of 65% but a high sensitivity of 85%, patients carrying a large spectrum of neurodegenerative diseases associated with cognitive deterioration (i.e., AD, frontotemporal lobar degeneration, Parkinson's disease with dementia, vascular dementia, mixed dementia, etc.) from subjects affected by other neurological disorders without mnesic disability; and (iii) is a neuronal injury biomarker as its levels in CSF are not related to the severity and progression of cognitive decline. The dynamic evaluation of NH2htau in CSF might add some useful hints in the ordinary clinical practice as it provides a novel, general biomarker for human tauopathies and other neurodegenerative diseases associated with dementia.
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PMID:Cerebrospinal fluid levels of a 20-22 kDa NH2 fragment of human tau provide a novel neuronal injury biomarker in Alzheimer's disease and other dementias. 2485 56