Clinical and pathological features of an Alzheimer's disease patient with the MAPT ΔK280 mutation

Momeni, Parastoo; Pittman, Alan; Lashley, Tammaryn; Vandrovcova, Jana; Malzer, Elke; Luk, Connie; Hulette, Christine M.; Lees, Andrew J.; Révész, Tamás; Hardy, John; Silva, Rohan de

doi:10.1016/j.neurobiolaging.2007.07.013

Cited by 57 publications

(42 citation statements)

References 22 publications

(29 reference statements)

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“…We included the following: (i) deletion of lysine 280 (ΔK280) (Rizzu et al ., 1999; Momeni et al ., 2009), which leads to excess of 3R transcripts (van Swieten et al ., 2007) and enhances tau aggregation into PHFs (Rizzu et al ., 1999; Barghorn et al ., 2000); (ii) mutations in cysteines 291 and 322 (C291 and C322), whose oxidation increases propensity of tau aggregation (Barghorn & Mandelkow, 2002; Mo et al ., 2009); and (iii) mutations that mimic or disrupt phosphorylation in residues previously related to tau toxicity or aggregation propensity (Biernat & Mandelkow, 1999). We have found that these modifications have a different impact on the degradation of tau by each of the autophagic pathways, and on the way in which they affect functioning of these autophagic pathways.…”

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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Section: Introductionmentioning

confidence: 99%

Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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“…The ⌬ K280 mutation has been described for several cases of FTDP-17 [12][13][14] . The mutation is enigmatic because on the mRNA level the mutation lies within exon 10 and favors the exclusion of this exon by alternative splicing, due to the disruption of an existing exon splicing enhancer [15] .…”

Section: Introductionmentioning

confidence: 99%

Generation of Tau Aggregates and Clearance by Autophagy in an Inducible Cell Model of Tauopathy

et al. 2010

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We have studied the mechanism of aggregation in an inducible cell model of Tau pathology. When the repeat domain of human Tau (Tau_RD) carrying the FTDP-17 mutation ΔK280 is expressed, the cells develop aggregates, as seen by thioflavin S fluorescence, electron microscopy, and sarkosyl extraction methods. By contrast, mutants of Tau_RD that are unable to generate β-structure do not aggregate. Enhanced aggregation leads to enhanced toxicity, visible by live cell microscopy and LDH release assay. The aggregation process is initiated by the sequential cleavage of Tau_RD which yields highly amyloidogenic fragments. This cleavage occurs only with proaggregant Tau_RD, and not with the nonaggregating mutants, indicating that β-structure makes Tau_RD vulnerable to both proteolytic degradation and aggregation. Aggregation is reversed by switching off the expression of Tau_RD, by inhibitor compounds, and by certain protease inhibitors. In all cases, the enhanced toxicity is rescued. The clearance of the aggregates involves autophagy, whereas proteasomal degradation plays only a minor role.

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“…Mutations within the repeat domain of the Tau protein can increase its β-sheet propensity (e.g., mutations P301L, ΔK280, and others), leading to missorting and aggregation of Tau (2,3). In humans, such mutations can cause typical FTLD pathology with corresponding neurofibrillary tangles (4). In transgenic mice expressing human Tau with the ΔK280 mutation, the Tau protein is missorted into the somatodendritic compartment, (hyper)phosphorylated, and folded into a pathological conformation (MC-1 epitope) (5).…”

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confidence: 99%

Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Dennissen

Anglada-Huguet

Sydow

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Accumulation of Tau is a characteristic hallmark of several neurodegenerative diseases but the mode of toxic action of Tau is poorly understood. Here, we show that the Tau protein is toxic due to its aggregation propensity, whereas phosphorylation and/or missorting is not sufficient to cause neuronal dysfunction. Aggregate-prone Tau accumulates, when expressed in vitro at near-endogenous levels, in axons as spindle-shaped grains. These axonal grains contain Tau that is folded in a pathological (MC-1) conformation. Proaggregant Tau induces a reduction of neuronal ATP, concomitant with loss of dendritic spines. Counterintuitively, axonal grains of Tau are not targeted for degradation and do not induce a molecular stress response. Proaggregant Tau causes neuronal and astrocytic hypoactivity and presynaptic dysfunction instead. Here, we show that the adenosine A 1 receptor antagonist rolofylline (KW-3902) is alleviating the presynaptic dysfunction and restores neuronal activity as well as dendritic spine levels in vitro. Oral administration of rolofylline for 2-wk to 14-mo-old proaggregant Tau transgenic mice restores the spatial memory deficits and normalizes the basic synaptic transmission. These findings make rolofylline an interesting candidate to combat the hypometabolism and neuronal dysfunction associated with Tau-induced neurodegenerative diseases.tauopathies | rolofylline | hypoactivity | axons | treatment

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Clinical and pathological features of an Alzheimer's disease patient with the MAPT ΔK280 mutation

Cited by 57 publications

References 22 publications

Interplay of pathogenic forms of human tau with different autophagic pathways

Interplay of pathogenic forms of human tau with different autophagic pathways

Generation of Tau Aggregates and Clearance by Autophagy in an Inducible Cell Model of Tauopathy

Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

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Clinical and pathological features of an Alzheimer's disease patient with the MAPT ΔK280 mutation

Cited by 57 publications

References 22 publications

Interplay of pathogenic forms of human tau with different autophagic pathways

Interplay of pathogenic forms of human tau with different autophagic pathways

Generation of Tau Aggregates and Clearance by Autophagy in an Inducible Cell Model of Tauopathy

Adenosine A 1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

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Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280