Abstract
IntroductionThe application of high-throughput genomic approaches has revealed 24 novel risk loci for Alzheimer’s disease (AD). We recently reported that the bridging integrator 1 (BIN1) risk gene is linked to Tau pathology.ResultsWe used glutathione S-transferase pull-down assays and nuclear magnetic resonance (NMR) experiments to demonstrate that BIN1 and Tau proteins interact directly and then map the interaction between BIN1’s SH3 domain and Tau’s proline-rich domain (PRD) . Our NMR data showed that Tau phosphorylation at Thr231 weakens the SH3-PRD interaction. Using primary neurons, we found that BIN1-Tau complexes partly co-localize with the actin cytoskeleton; however, these complexes were not observed with Thr231-phosphorylated Tau species.ConclusionOur results show that (i) BIN1 and Tau bind through an SH3-PRD interaction and (ii) the interaction is downregulated by phosphorylation of Tau Thr231 (and potentially other residues). Our study sheds new light on regulation of the BIN1/Tau interaction and opens up new avenues for exploring its complex’s role in the pathogenesis of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0237-8) contains supplementary material, which is available to authorized users.
Highlights
The application of high-throughput genomic approaches has revealed 24 novel risk loci for Alzheimer’s disease (AD)
Our results provide a detailed view of the molecular interplay between Tau and bridging integrator 1 (BIN1) and show for the first time that Tau phosphorylation weakens the interaction between these two proteins
Tau’s phosphorylation status influences BIN1-Tau binding in primary neurons Since we had observed that Tau phosphorylation within or close to the Tau/proline-rich domain (PRD) was able to modulate the BIN1-Tau interaction in vitro, we looked at whether phosphorylation might modulate the interaction in primary neurons
Summary
The application of high-throughput genomic approaches has revealed 24 novel risk loci for Alzheimer’s disease (AD). Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder characterized by (i) the massive loss of neurons in several regions of the brain. Mutations in the genes for amyloid precursor protein (APP), presenilin and presenilin-2 are responsible for rare, autosomaldominant forms of AD. The discovery of these mutations prompted the amyloid cascade hypothesis, which has radically changed our understanding of AD; APP metabolism and Aβ peptide production/degradation are thought to Sottejeau et al Acta Neuropathologica Communications (2015) 3:58 suggest that BIN1 interacts with Tau and is involved in Tau pathology. Our results provide a detailed view of the molecular interplay between Tau and BIN1 and show for the first time that Tau phosphorylation weakens the interaction between these two proteins
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