Stages and Conformations of the Tau Repeat Domain during Aggregation and Its Effect on Neuronal Toxicity
- Journal Article
Rights / licenseCreative Commons Attribution 4.0 International
Several neurodegenerative diseases are characterized by the aggregation and posttranslational modifications of Tau protein. Its “repeat domain” (TauRD) is mainly responsible for the aggregation properties, and oligomeric forms are thought to dominate the toxic effects of Tau. Here we investigated the conformational transitions of this domain during oligomerization and aggregation in different states of β-propensity and pseudo-phosphorylation, using several complementary imaging and spectroscopic methods. Although the repeat domain generally aggregates more readily than full-length Tau, its aggregation was greatly slowed down by phosphorylation or pseudo-phosphorylation at the KXGS motifs, concomitant with an extended phase of oligomerization. Analogous effects were observed with pro-aggregant variants of TauRD. Oligomers became most evident in the case of the pro-aggregant mutant TauRDΔK280, as monitored by atomic force microscopy, and the fluorescence lifetime of Alexa-labeled Tau (time-correlated single photon counting (TCSPC)), consistent with its pronounced toxicity in mouse models. In cell models or primary neurons, neither oligomers nor fibrils of TauRD or TauRDΔK280 had a toxic effect, as seen by assays with lactate dehydrogenase and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, respectively. However, oligomers of pro-aggregant TauRDΔK280 specifically caused a loss of spine density in differentiated neurons, indicating a locally restricted impairment of function. Show more
Journal / seriesJournal of Biological Chemistry
Pages / Article No.
PublisherThe American Society for Biochemistry and Molecular Biology
SubjectAggregation; Neuron; Phosphorylation; Synapse; Tau Protein (Tau); Oligomers; Time-correlated Single Photon Counting; Toxicity
Organisational unit03870 - Müller, Daniel J. / Müller, Daniel J.
NotesReceived for publication,February 6, 2014, and in revised form, May 5, 2014 Published,.
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