Tau domains, phosphorylation, and interactions with microtubules

Mandelkow, Eva‐Maria; Biernat, Jacek; Drewes, Gerard; Gustke, N.; Trinczek, Bernhard

doi:10.1016/0197-4580(95)00025-a

Cited by 281 publications

(208 citation statements)

References 40 publications

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“…Phosphorylation has been extensively studied in the context of tau pathology (Mandelkow et al ., 1995; Wang & Mandelkow, 2016), but due to the multiplicity of phosphorylation sites in the protein, the site‐specific impact of phosphorylation on tau biology is not well understood. We chose to analyze the effect of mutations that mimic phosphorylation at specific residues that form part of the epitopes of antibodies elevated in AD or for which an aggregation propensity has been described (Biernat & Mandelkow, 1999; Chang et al ., 2011; Combs et al ., 2011; Kiris et al ., 2011; Prokopovich et al ., 2017, 50).…”

Section: Resultsmentioning

confidence: 99%

Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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SummaryLoss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule‐stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients’ brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

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Section: Resultsmentioning

confidence: 99%

Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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“…In contrast, in adult humans exon 10 remains regulated in the central nervous system where the two possible isoforms (10 + and 10 − ) are present in a 1:1 ratio (Gao et al, 2000;Goedert et al, 1989b). The domain encoded by exon 10 increases the affinity of tau protein to microtubules and may be important in the transition from the more fluid fetal cytoskeleton to the more stable adult one (Himmler et al, 1989;Lee et al, 1989;Mandelkow et al, 1995). Misregulation of tau exon 10 splicing causes inherited frontotemporal dementia with Parkinsonism (FTDP-17; Goedert and Jakes, 2005).…”

Section: Introductionmentioning

confidence: 99%

SR protein 9G8 modulates splicing of tau exon 10 via its proximal downstream intron, a clustering region for frontotemporal dementia mutations

Gao

Wang

et al. 2007

Molecular and Cellular Neuroscience

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The microtubule-associated protein tau is important to normal neuronal function in the mammalian nervous system. Aggregated tau is the major component of neurofibrillary tangles (NFTs), present in several neurodegenerative diseases, including Alzheimer's and frontotemporal dementia with Parkinsonism (FTDP). Splicing misregulation of adult-specific exon 10 results in expression of abnormal ratios of tau isoforms, leading to FTDP. Positions +3 to +16 of the intron downstream of exon 10 define a clustering region for point mutations that are found in FTDP. The serine/argininerich (SR) factor 9G8 strongly inhibits inclusion of tau exon 10. In this study, we established that 9G8 binds directly to this clustering region, requires a wild-type residue at position +14 to inhibit exon inclusion, and RNAi constructs against 9G8 increase exon 10 inclusion. These results indicate that 9G8 plays a key role in regulation of exon 10 splicing and imply a pathogenic role in neurodegenerative diseases.

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“…[16][17][18][19] Among these kinases, cdk5-a serine-threonine protein kinase, as well as its cyclin-related activator molecules p35, p39, p25, and p29 20 -has been demonstrated to phosphorylate tau at sites implicated in AD pathology. 21,22 Among the many sites phosphorylated in PHF tau are serine 396 and serine 404. 23 PHF-1 is a monoclonal antibody 24 directed against the phosphorylated tau epitope formed by serine 396 and serine 404.…”

Section: Introductionmentioning

confidence: 99%

Development of an Assay to Screen for Inhibitors of Tau Phosphorylation by Cdk5

et al. 2004

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A high-throughput assay for tau phosphorylation by cdk5/p25 is described. Full-length recombinant tau was used as a substrate in the presence of saturating adenosine triphosphate (ATP). Using PHF-1, an antibody directed specifically against 2 tau phosphorylation epitopes (serine 396 and serine 404), an enzyme-linked immunosorbent assay (ELISA)-based colorimetric assay was formatted in 384-well plates. The assay was validated by measuring kinetic parameters for cdk5/p25 catalysis and known inhibitors. Rate constants for the site-specific phosphorylations at the PHF-1 epitopes were determined and suggested preferential phosphorylation at these sites. The performance of this assay in a high-throughput format was demonstrated and used to identify inhibitors of tau phosphorylation at specific epitopes phosphorylated by cdk5/p25. (Journal of Biomolecular Screening 2004:122-131)

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Tau domains, phosphorylation, and interactions with microtubules

Cited by 281 publications

References 40 publications

Interplay of pathogenic forms of human tau with different autophagic pathways

Interplay of pathogenic forms of human tau with different autophagic pathways

SR protein 9G8 modulates splicing of tau exon 10 via its proximal downstream intron, a clustering region for frontotemporal dementia mutations

Development of an Assay to Screen for Inhibitors of Tau Phosphorylation by Cdk5

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