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Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase regulating diverse cellular functions including metabolism, transcription and cell survival. Numerous intracellular signalling pathways converge on GSK-3 and regulate its activity via inhibitory serine-phosphorylation. Recently, GSK-3 has been involved in learning and memory and in(More)
The morphology of a neuron is determined by its cytoskeletal scaffolding. Thus proteins that associate with the principal cytoskeletal components such as the microtubules have a strong influence on both the morphology and physiology of neurons. Tau is a microtubule-associated protein that stabilizes neuronal microtubules under normal physiological(More)
Glycogen synthase kinase-3beta (GSK-3beta) has been postulated to mediate Alzheimer's disease tau hyperphosphorylation, beta-amyloid-induced neurotoxicity and presenilin-1 mutation pathogenic effects. By using the tet-regulated system we have produced conditional transgenic mice overexpressing GSK-3beta in the brain during adulthood while avoiding perinatal(More)
Collapsin response mediator proteins (CRMPs) are a family of neuron-enriched proteins that regulate neurite outgrowth and growth cone dynamics. Here, we show that Cdk5 phosphorylates CRMP1, CRMP2, and CRMP4, priming for subsequent phosphorylation by GSK3 in vitro. In contrast, DYRK2 phosphorylates and primes CRMP4 only. The Cdk5 and DYRK2 inhibitor(More)
An imbalance of tau isoforms containing either three or four microtubule-binding repeats causes frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) in families with intronic mutations in the MAPT gene. Here we report equivalent imbalances at the mRNA and protein levels and increased total tau levels in the brains of subjects with(More)
Tau is a neuronal microtubule-associated phosphoprotein that is highly phosphorylated by glycogen synthase kinase 3 (GSK3). Tau phosphorylation by GSK3 regulates tau binding to microtubules, tau degradation and tau aggregation. Tau phosphorylation is important in Alzheimer disease pathology and in other tauopathies. In Alzheimer disease, it has been(More)
Deregulation of glycogen synthase kinase-3 (GSK-3) activity in neurones has been postulated as a key feature in Alzheimer's disease (AD) pathogenesis. This was further supported by our recent characterization of transgenic mice that conditionally over-express GSK-3beta in hippocampal and cortical neurones. These mice, designated Tet/GSK-3beta, showed many(More)
Huntington's disease (HD) inclusions are stained with anti-ubiquitin and anti-proteasome antibodies. This, together with proteasome activity studies on transfected cells, suggest that an impairment of the ubiquitin-proteasome system (UPS) may be key in HD pathogenesis. To test whether proteasome activity is impaired in vivo, we performed enzymatic assays(More)
Increased glycogen synthase kinase-3 (GSK-3) activity is believed to contribute to the etiology of chronic disorders like Alzheimer's disease and diabetes, thus supporting therapeutic potential of GSK-3 inhibitors. However, sustained GSK-3 inhibition might induce tumorigenesis through beta-catenin-APC dysregulation. Besides, sustained in vivo inhibition by(More)
The tauopathies, which include Alzheimer's disease (AD) and frontotemporal dementias, are a group of neurodegenerative disorders characterized by filamentous Tau aggregates. That Tau dysfunction can cause neurodegeneration is indicated by pathogenic tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). To investigate(More)