Several mutations in the gene encoding the microtubule-associated protein tau are responsible for... more Several mutations in the gene encoding the microtubule-associated protein tau are responsible for the formation of neurofibrillary inclusions in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here we present the high-resolution characterization of the conformational properties of two FTDP-17 mutants of the four-repeat domain of tau, P301L and DeltaK280, and their properties for binding to polyanions and microtubules. Multidimensional NMR spectroscopy shows that the mutations do no lead to a significant increase in the level of beta-structure in their monomeric state, even though the mutations strongly promote beta-structure during aggregation. However, local structural changes are induced in the second repeat. These changes only weakly affect the binding to the polyanion heparin, which promotes paired helical filament formation. The extent of binding to microtubules, however, is strongly decreased. Our results demonstrate that the reversible binding of tau to microtubules involves specific interactions, which are not essential for binding to polyanions.
The experiments were carried out on 80 male Wistar rats, divided into four groups as follows: gro... more The experiments were carried out on 80 male Wistar rats, divided into four groups as follows: group 1, treated orally with ZnCl2 at a dose of 10 mg Zn2+/kg for 14 days; group 2, control; group 3, MgCl2-treated at a dose of 5 mg Mg2+/kg; group 4, treated with ZnCl2 plus MgCl2 in the same manner as groups 1 and 3. The influx of calcium into the rat duodenum slices was investigated in vitro by the method of Papworth and Patrick. Over a range of calcium concentrations (0–10 mM) the influx of this element was defined as a sum of a saturable term (active transport) and a linear term dependent on concentration (passive transport). In the zinc-treated rats only the saturable term was affected. The study of this term by Lineweaver-Burk plots showed a decrease of the half-saturation constant,K t, while the maximal value,J m, remained unchanged. Moreover, magnesium was shown to interact with zinc at gut level because simultaneous oral administration of Mg2+ and Zn2+ to rats protected them against the inhibition of calcium uptake observed when Zn2+ was given alone.
Several mutations in the gene encoding the microtubule-associated protein tau are responsible for... more Several mutations in the gene encoding the microtubule-associated protein tau are responsible for the formation of neurofibrillary inclusions in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here we present the high-resolution characterization of the conformational properties of two FTDP-17 mutants of the four-repeat domain of tau, P301L and DeltaK280, and their properties for binding to polyanions and microtubules. Multidimensional NMR spectroscopy shows that the mutations do no lead to a significant increase in the level of beta-structure in their monomeric state, even though the mutations strongly promote beta-structure during aggregation. However, local structural changes are induced in the second repeat. These changes only weakly affect the binding to the polyanion heparin, which promotes paired helical filament formation. The extent of binding to microtubules, however, is strongly decreased. Our results demonstrate that the reversible binding of tau to microtubules involves specific interactions, which are not essential for binding to polyanions.
The experiments were carried out on 80 male Wistar rats, divided into four groups as follows: gro... more The experiments were carried out on 80 male Wistar rats, divided into four groups as follows: group 1, treated orally with ZnCl2 at a dose of 10 mg Zn2+/kg for 14 days; group 2, control; group 3, MgCl2-treated at a dose of 5 mg Mg2+/kg; group 4, treated with ZnCl2 plus MgCl2 in the same manner as groups 1 and 3. The influx of calcium into the rat duodenum slices was investigated in vitro by the method of Papworth and Patrick. Over a range of calcium concentrations (0–10 mM) the influx of this element was defined as a sum of a saturable term (active transport) and a linear term dependent on concentration (passive transport). In the zinc-treated rats only the saturable term was affected. The study of this term by Lineweaver-Burk plots showed a decrease of the half-saturation constant,K t, while the maximal value,J m, remained unchanged. Moreover, magnesium was shown to interact with zinc at gut level because simultaneous oral administration of Mg2+ and Zn2+ to rats protected them against the inhibition of calcium uptake observed when Zn2+ was given alone.
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Papers by Aleksandra Witkowska