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1.
Brain Neurosci Adv ; 2: 2398212818799248, 2018.
Article in English | MEDLINE | ID: mdl-32166148

ABSTRACT

As the British Neuroscience Association commemorates 50 years of existence in 2018, this article recalls its founding as a discussion group, its establishment as the Brain Research Association, its transition to a professional society encompassing all aspects of neuroscience research, both clinical and non-clinical, and its re-branding as the British Neuroscience Association in the late 1990s. Neuroscience as a branch of life science has expanded hugely in the last 25 years and the British Neuroscience Association has adapted, frequently working with partner societies, to serve as an interdisciplinary hub for professionals working in this exciting and crucial field. The authors have attempted to highlight some key events in the Association's history and acknowledge the contributions made by many people over half a century.

2.
J Biol Chem ; 283(26): 18177-86, 2008 Jun 27.
Article in English | MEDLINE | ID: mdl-18467332

ABSTRACT

The microtubule-associated protein tau can associate with various other proteins in addition to tubulin, including the SH3 domains of Src family tyrosine kinases. Tau is well known to aggregate to form hyperphosphorylated filamentous deposits in several neurodegenerative diseases (tauopathies) including Alzheimer disease. We now report that tau can bind to SH3 domains derived from the p85alpha subunit of phosphatidylinositol 3-kinase, phospholipase Cgamma1, and the N-terminal (but not the C-terminal) SH3 of Grb2 as well as to the kinases Fyn, cSrc, and Fgr. However, the short inserts found in neuron-specific isoforms of Src prevented the binding of tau. The experimentally determined binding of tau peptides is well accounted for when modeled into the peptide binding cleft in the SH3 domain of Fyn. After phosphorylation in vitro or in transfected cells, tau showed reduced binding to SH3 domains; no binding was detected with hyperphosphorylated tau isolated from Alzheimer brain, but SH3 binding was restored by phosphatase treatment. Tau mutants with serines and threonines replaced by glutamate, to mimic phosphorylation, showed reduced SH3 binding. These results strongly suggest that tau has a potential role in cell signaling in addition to its accepted role in cytoskeletal assembly, with regulation by phosphorylation that may be disrupted in the tauopathies including Alzheimer disease.


Subject(s)
GRB2 Adaptor Protein/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phospholipase C gamma/metabolism , src-Family Kinases/metabolism , tau Proteins/chemistry , Alzheimer Disease/metabolism , Amino Acid Sequence , Humans , Molecular Conformation , Molecular Sequence Data , Peptides/chemistry , Phosphorylation , Protein Binding , Protein Structure, Tertiary , src Homology Domains
3.
Proteomics ; 8(6): 1221-36, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18283660

ABSTRACT

Accumulation of proteins in inclusions in neurological disorders is partly due to dysfunction of the ubiquitin-proteasome system. Proteasomal dysfunction may be caused by misexpression of one or more of its subunits. A large number of antibodies reactive with proteasome subunits were screened on material from patients exhibiting tau- and synucleinopathies. Many antisera against proteasomal subunits (11S activator, 19S regulator ATPase/non-ATPase, and 20S alpha and beta resulted in a distinct nuclear and/or cytoplasmic staining of the entorhinal-hippocampal area and the temporal cortex of Alzheimer's disease (AD) patients. In particular an antibody directed against 19S regulator ATPase subunit 6b (S6b) specifically stained the neurofibrillary tangles and dystrophic neurites in AD, Down syndrome and aged nondemented controls. In other tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy and argyrophilic grain disease), neuronal and/or glial inclusions were also S6b immunoreactive. In contrast, in synucleinopathies (Lewy body disease (LBD) and multiple system atrophy) no S6b staining was seen. Real time quantitative PCR on the temporal cortex of AD patients revealed a significant increase in S6b subunit mRNA. This increase was not found in the gyrus cinguli anterior of patients with LBD. This differential expression of S6b most likely will result in different proteomic patterns. Here we present evidence to show that S6b coexists with a reporter for proteasomal dysfunction (ubiquitin(+1)), and we conclude that S6b transcript up-regulation and the dysfunction in tauopathies may be functionally related.


Subject(s)
Proteasome Endopeptidase Complex/metabolism , Proteomics/methods , Synucleins/metabolism , Tauopathies/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Antibodies/immunology , Gene Expression , Humans , Immunohistochemistry , Lewy Body Disease/metabolism , Lewy Body Disease/pathology , Models, Biological , Multiple System Atrophy/metabolism , Multiple System Atrophy/pathology , Pick Disease of the Brain/metabolism , Pick Disease of the Brain/pathology , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/immunology , Protein Subunits/genetics , Protein Subunits/immunology , Protein Subunits/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tauopathies/pathology , Temporal Lobe/metabolism , Temporal Lobe/pathology
4.
J Neurosci ; 22(1): 10-20, 2002 Jan 01.
Article in English | MEDLINE | ID: mdl-11756483

ABSTRACT

The increased production of amyloid beta-peptide (Abeta) in Alzheimer's disease is acknowledged to be a key pathogenic event. In this study, we examined the response of primary human and rat brain cortical cultures to Abeta administration and found a marked increase in the tyrosine phosphorylation content of numerous neuronal proteins, including tau and putative microtubule-associated protein 2c (MAP2c). We also found that paired helical filaments of aggregated and hyperphosphorylated tau are tyrosine phosphorylated, indicating that changes in the phosphotyrosine content of cytoplasmic proteins in response to Abeta are potentially an important process. Increased tyrosine phosphorylation of cytoskeletal and other neuronal proteins was specific to fibrillar Abeta(25-35) and Abeta(1-42). The tyrosine phosphorylation was blocked by addition of the Src family tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4-d)pyramide (PP2) and the phosphatidylinositol 3-kinase inhibitor LY 294002. Tyrosine phosphorylation of tau and MAP2c was concomitant with an increase in the tyrosine phosphorylation and subsequent putative activation of the non-receptor kinase, focal adhesion kinase (FAK). Immunoprecipitation of Fyn, a member of the Src family, from Abeta(25-35)-treated neurons showed an increased association of Fyn with FAK. Abeta treatment of cells also stimulated the sustained activation of extracellular regulated kinase-2, which was blocked by addition of PP2 and LY 294002, suggesting that FAK/Fyn/PI3-kinase association is upstream of mitogen-activated protein (MAP) kinase signaling in Abeta-treated neurons. This cascade of signaling events contains the earliest biochemical changes in neurons to be described in response to Abeta exposure and may be critical for subsequent neurodegenerative changes.


Subject(s)
Amyloid beta-Peptides/pharmacology , Neurons/metabolism , Protein-Tyrosine Kinases/metabolism , src-Family Kinases/metabolism , tau Proteins/metabolism , Animals , Caspases/metabolism , Cells, Cultured , Cytoskeletal Proteins/metabolism , Enzyme Inhibitors/pharmacology , Focal Adhesion Kinase 1 , Focal Adhesion Protein-Tyrosine Kinases , Humans , Microtubule-Associated Proteins/metabolism , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Neurons/cytology , Neurons/drug effects , Peptide Fragments/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation/drug effects , Protein Binding/drug effects , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-fyn , Rats , Signal Transduction/drug effects , Signal Transduction/physiology , Tyrosine/metabolism , src-Family Kinases/antagonists & inhibitors
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