Sites of phosphorylation in tau and factors affecting their regulation

Anderton, Brian H.; Betts, Joanna; Blackstock, Walter; Brion, Jean Pierre; Chapman, Steve; Connell, James W.; Dayanandan, R; Gallo, Jean-Marc; Gibb, G M; Hanger, Diane P.; Hutton, Michael; Kardalinou, E; Leroy, Karelle; Lovestone, Simon; Mack, Till G. A.; Reynolds, C. Hugh; Slegtenhorst, Marjon van; O'Neil, Crystal L.

doi:10.1042/bst028a015b

Cited by 29 publications

(34 citation statements)

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“…1C). 66 Pathologic hyperphosphorylation might thus lead to tau-microtubule detachment, subsequent instability of microtubule networks, impaired axonal transport and synaptic degeneration (FIG. 4).…”

Section: Pathophysiologymentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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Section: Pathophysiologymentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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“…p35 and p39 can be proteolyzed by the calcium-dependent protease calpain (Kusakawa et al, 2000;Patzke and Tsai, 2002), resulting in p25 and p29, respectively, which are more stable than p35 or p39 and thus cause a more prolonged activation of Cdk5 (Kusakawa et al, 2000;Patrick et al, 1998;Patrick et al, 1999;Patzke and Tsai, 2002). In vitro, tau is a substrate of Cdk5, and most if not all of the sites on tau that are phosphorylated by Cdk5 are also phosphorylated by GSK3β (Anderton et al, 2001;Hashiguchi et al, 2002;Liu et al, 2002;Lund et al, 2001). Overexpression of Cdk5 and p25, but not p35, results in increased tau phosphorylation at specific sites (Hamdane et al, 2003;Patrick et al, 1999).…”

Section: Kinases That Regulate Tau Phosphorylation In Vivomentioning

confidence: 99%

Tau phosphorylation in neuronal cell function and dysfunction

Johnson

Stoothoff

2004

Journal of Cell Science

517

413

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Tau is a group of neuronal microtubule-associated proteins that are formed by alternative mRNA splicing and accumulate in neurofibrillary tangles in Alzheimer's disease (AD) brain. Tau plays a key role in regulating microtubule dynamics, axonal transport and neurite outgrowth, and all these functions of tau are modulated by site-specific phosphorylation. There is significant evidence that a disruption of normal phosphorylation events results in tau dysfunction in neurodegenerative diseases, such as AD, and is a contributing factor to the pathogenic processes. Indeed, the abnormal tau phosphorylation that occurs in neurodegenerative conditions not only results in a toxic loss of function (e.g. decreased microtubule binding) but probably also a toxic gain of function (e.g. increased tau-tau interactions). Although tau is phosphorylated in vitro by numerous protein kinases, how many of these actually phosphorylate tau in vivo is unclear. Identification of the protein kinases that phosphorylate tau in vivo in both physiological and pathological processes could provide potential therapeutic targets for the treatment of AD and other neurodegenerative diseases in which there is tau pathology.

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“…Both kinases phosphorylate tau at a large number of sites, most of which are common to the two enzymes (Wang et al, 1998;Anderton et al, 2001). Moreover, CDK5 and GSK3␤ are the key kinases responsible for the APP phosphorylation (Aplin et al, 1996;Iijima et al, 2000).…”

Section: Atra Prevents App Processing and Phosphorylation Of Both Appmentioning

confidence: 99%

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Ding¹,

et al. 2008

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Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to ␤-amyloid (A␤) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain A␤ deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/ PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.

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Sites of phosphorylation in tau and factors affecting their regulation

Cited by 29 publications

References 0 publications

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Tau phosphorylation in neuronal cell function and dysfunction

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

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