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Neuron. 2018 Feb 21;97(4):823-835.e8. doi: 10.1016/j.neuron.2018.01.022. Epub 2018 Feb 1.

Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau.

Author information

1
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences and Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium.
2
Institute of Neuroscience, Alzheimer Dementia Group, Catholic University of Louvain, 1200 Brussels, Belgium; Biomedical Research Institute, Hasselt University, 3500 Hasselt, Belgium.
3
VIB-UGent Center for Medical Biotechnology, 9000 Ghent, Belgium; Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
4
UK Dementia Research Institute, Euan MacDonald Centre, and Centre for Dementia Prevention, Edinburgh Neuroscience, University of Edinburgh, Edinburgh EH8 9JZ, UK.
5
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences and Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium; Dementia Research Institute, University College London, London WC1E 6BT, UK.
6
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences and Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium. Electronic address: patrik.verstreken@kuleuven.vib.be.

Abstract

Synaptic dysfunction is an early pathological feature of neurodegenerative diseases associated with Tau, including Alzheimer's disease. Interfering with early synaptic dysfunction may be therapeutically beneficial to prevent cognitive decline and disease progression, but the mechanisms underlying synaptic defects associated with Tau are unclear. In disease conditions, Tau mislocalizes into pre- and postsynaptic compartments; here we show that, under pathological conditions, Tau binds to presynaptic vesicles in Alzheimer's disease patient brain. We define that the binding of Tau to synaptic vesicles is mediated by the transmembrane vesicle protein Synaptogyrin-3. In fly and mouse models of Tauopathy, reduction of Synaptogyrin-3 prevents the association of presynaptic Tau with vesicles, alleviates Tau-induced defects in vesicle mobility, and restores neurotransmitter release. This work therefore identifies Synaptogyrin-3 as the binding partner of Tau on synaptic vesicles, revealing a new presynapse-specific Tau interactor, which may contribute to early synaptic dysfunction in neurodegenerative diseases associated with Tau.

KEYWORDS:

Alzheimer’s disease; Synaptogyrin-3; Syngr3; Tau; Tauopathy; neurodegeneration; presynapse; synapse; synaptic dysfunction; synaptic vesicles

PMID:
29398363
DOI:
10.1016/j.neuron.2018.01.022
[Indexed for MEDLINE]
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