Article
Reference
Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects
LATHUILIERE, Aurélien, et al.
Abstract
Tau pathology is associated with cognitive decline in Alzheimer's disease, and missense tau mutations cause frontotemporal dementia. Hyperphosphorylation and misfolding of tau are considered critical steps leading to tauopathies. Here, we determine how motifs controlling conformational changes in the microtubule-binding domain determine tau pathology in vivo.
Human tau was overexpressed in the adult mouse forebrain to compare variants carrying residues that modulate tau propensity to acquire a β-sheet conformation. The P301S mutation linked to frontotemporal dementia causes tau aggregation and rapidly progressing motor deficits. By comparison, wild-type tau becomes heavily hyperphosphorylated, and induces behavioral impairments that do not progress over time. However, the behavioral defects caused by wild-type tau can be suppressed when β-sheet breaking proline residues are introduced in the microtubule-binding domain of tau. This modification facilitates tau interaction with microtubules, as shown by lower levels of phosphorylation, and by the enhanced protective effects of mutated tau against the severing of the [...]
LATHUILIERE, Aurélien, et al. Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects. Scientific reports, 2017, vol. 7, no. 1, p. 13556
DOI : 10.1038/s41598-017-13786-2 PMID : 29051562
PMCID : PMC5648870
Available at:
http://archive-ouverte.unige.ch/unige:155607
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Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects
Aurélien Lathuilière1#, Pamela Valdés1#, Stéphanie Papin2,4, Matthias Cacquevel1, Catherine Maclachlan3, Graham W. Knott3, Andreas Muhs2, Paolo Paganetti2,4, Bernard L. Schneider1*
Supplementary information
Supplementary Figure S1Supplementary Figure S2
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Supplementary Figure S1. Total tau expression in the forebrain of mice injected with AAV-tau
The amount of total tau protein (mouse and human) is assessed by western blot using the Tau5 antibody in mouse forebrain protein homogenates at 1.5 and 7 months after vector injection. Ct: control AAV-maxFP injection. Protein extracts from human brain cortex from a control (Human Ct) and Alzheimer’s patient (Human AD) are shown in the last two lanes for comparison. Actin is shown as loading control.
Supplementary Figure S1
Tau5
Actin
Ct P301S P301STau WT Tau WT Human Ct Human AD
months1.5 7 months
60 44 37 kDa
44 37
3
Supplementary Figure S2. Human tau overexpression triggers neurodegeneration in mouse cortex
a) Representative cresyl violet staining in sagittal brain sections, 3 months after AAV injection. Arrows indicate an evident thinning of the cortex observed in the mice injected with AAV-WT and AAV-P301S. Scale bar: 1 mm. b) Representative NeuN immunolabeling in a sagittal brain section of an AAV-WT injected mouse. Cortical layers are indicated by roman numerals. Note the extensive degeneration of the most superficial cortical layers.
Scale bar: 500 µm.
a
Tau P301S Tau WT
Control
b
II/IIII IV V VI
Tau WT
Tau 2P
