Association of missense and 5′-splice-site mutations in tau  with the inherited dementia FTDP-17

Hutton, Michael; Lendon, Corinne; Rizzu, Patrizia; Baker, Matt; Froelich, Susanne; Houlden, Henry; Pickering‐Brown, Stuart; Chakraverty, Sumi; Isaacs, Adrian M.; Grover, Andrew; Hackett, J.M.; Adamson, Jennifer; Lincoln, Sarah; Dickson, Dennis W.; Davies, Peter; Petersen, Ron; Stevens, Martijn; Graaff, Esther de; Wauters, Erwin; Baren, J. Van; Hillebrand, Marcel; Joosse, Marijke; Kwon, Jennifer M.; Nowotny, Petra; Kuei, Lien; Norton, Joanne; Morris, John C.; Reed, Lee A.; Trojanowski, John Q.; Basun, Hans; Lannfelt, Lars; Neystat, M.; Fahn, Stanley; Dark, Frances; Tannenberg, Tony; Dodd, Peter R.; Hayward, Nick; Kwok, John B.; Schofield, Peter R.; Andreadis, Athena; Snowden, Julie S.; Craufurd, David; Neary, David; Owen, F.; Oostra, Ben A.; Hardy, John; Goate, Alison M.; Swieten, John van; Mann, David; Lynch, Timothy; Heutink, Peter

doi:10.1038/31508

Cited by 3,160 publications

(2,294 citation statements)

References 27 publications

(46 reference statements)

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“…Reflecting astrocytic metabolism, the percentage enrichment of [4,[5][6][7][8][9][10][11][12][13] C]glutamate, [4,[5][6][7][8][9][10][11][12][13] C]glutamine and [1,2-13 C]GABA were significantly increased in the cerebral cortex of pR5 mice compared with controls ( Figure 2B). Calculation of M þ 2 isotopomers from NMRS results demonstrated that the percentage enrichment of M þ 2 glutamate and glutamine were increased, whereas that of M þ 2 GABA remained unaltered (Table 3).…”

Section: Concentrations Of Metabolitesmentioning

confidence: 99%

Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

Nilsen

Rae

Ittner

et al. 2013

J Cereb Blood Flow Metab

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In neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia, the protein tau is hyperphosphorylated and eventually aggregates to develop neurofibrillary tangles. Here, the consequences of tau hyperphosphorylation on both neuronal and astrocytic metabolism and amino-acid neurotransmitter homeostasis were assessed in transgenic mice expressing the pathogenic mutation P301L in the human tau gene (pR5 mice) compared with nontransgenic littermate controls. Mice were injected with the neuronal and astrocytic substrate [1-13 C]glucose and the astrocytic substrate [1,2-13 C]acetate. Hippocampus and cerebral cortex extracts were analyzed using 1 H and 13 C nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry and high-performance liquid chromatography. The glutamate level was reduced in the hippocampus of pR5 mice, accompanied by reduced incorporation of 13 C label derived from [1-13 C]glucose in glutamate. In the cerebral cortex, glucose utilization as well as turnover of glutamate, glutamine, and GABA, were increased. This was accompanied by a relative increase in production of glutamate via the pyruvate carboxylation pathway in cortex. Overall, we revealed that astrocytes as well as glutamatergic and GABAergic neurons in the cortex of pR5 mice were in a hypermetabolic state, whereas in the hippocampus, where expression levels of mutant human tau are the highest, glutamate homeostasis was impaired.

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Section: Concentrations Of Metabolitesmentioning

confidence: 99%

Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

Nilsen

Rae

Ittner

et al. 2013

J Cereb Blood Flow Metab

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“…We first compared two different mutations: P301L, known to cause autosomal‐dominant frontotemporal dementia (FTD) (Hutton et al ., 1998); and a point mutation of tau (A152T) that does not cause autosomal‐dominant disease but associates with higher risk of frontotemporal dementia and Alzheimer's disease (AD) (Coppola et al ., 2012). Our work reveals that both mutant forms of tau become poor e‐MI substrates and that P301L mutation, in addition, markedly reduces tau's susceptibility for CMA degradation.…”

Section: Introductionmentioning

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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“…The presence of hyperphosphorylated filamentous tau is a feature of several neurodegenerative disorders such as Alzheimer's disease, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17T), progressive sopranuclear palsy, and others that are collectively designated as tauopathies (Spillantini and Goedert, 2013). The dysfunction of tau is sufficient to cause neurodegeneration, as shown in FTDP‐17T that is caused by mutations in the MAPT gene (Spillantini et al, 1998; Hutton et al, 1998). …”

Section: Introductionmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule‐associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau‐induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S‐htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2‐month‐old P301S‐htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL‐1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S‐htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S‐htau axons to demyelination‐induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S‐htau mice compared with Wt mice‐derived OPCs. Because the OPCs from P301S‐htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice‐derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2016;64:457–471

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Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17

Cited by 3,160 publications

References 27 publications

Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

Interplay of pathogenic forms of human tau with different autophagic pathways

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

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