Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau

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.

Altered levels of plasma neuron‐derived exosomes and their cargo proteins characterize acute and chronic mild traumatic brain injury

“…1). Synaptogyrin‐3 is a protein of presynaptic vesicles that has the highest affinity for tau/P‐tau of all synaptic proteins examined and whose binding of tau restricts synaptic vesicle mobility with consequent neural dysfunction (42). NDE levels of synaptogyrin‐3 were significantly higher after acute mTBI and marginally higher in chronic mTBI than for controls (Fig.…”

“…Similarly, our finding of a higher than normal mean NDE level of synaptogyrin‐3 many months after the last episode of acute mTBI suggest its possible role in the progression to chronic mTBI. The synaptogyrin‐3 in presynaptic vesicles binds tau in brain tissues of neurodegenerative diseases so that tau may more effectively mediate vesicle clustering, diminish vesicle mobility, and impair neurotransmission (42). Our tentative integration of evolving data suggest that elevated NDE levels of Aβ42, P‐T181‐tau, and P‐S396‐tau in chronic mTBI reflect their direct contributions to the proteinopathic neurodegeneration of CTE.…”

Activity-dependent nucleation of dynamic microtubules at presynaptic boutons is required for neurotransmission

“…One hypothesis is that neuronal firing may drive Ca 2+ influx dependent recruitment of MT nucleation complexes only at active boutons. Given the critical role that loss of a functional presynaptically-localized machinery for MT nucleation may have for neurotransmission, it will be important to determine the in vivo significance of this selective MT nucleation and whether dysregulation of this process can be associated with human neurological and neuropsychiatric illnesses caused by mutations in MT regulatory proteins residing presynaptically, such as tau in AD (40,41) and tauopathies, spastin in hereditary spastic paraplegias (42,43), and MAP1B and FMRP in Fragile X Syndrome (44-46).…”

Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

“…While many of the proposed mechanisms of synapse degeneration focus on post-synaptic processes, our data clearly show accumulation of both Aß and tau in pre as well as postsynaptic terminals. Tau has recently been shown to bind to presynaptic vesicles in human AD and Drosophila models, where it impairs neurotransmitter release (McInnes et al, 2018;Zhou et al, 2017). Similarly, it is also becoming clear that Aß exerts effects on presynaptic function (Ovsepian et al, 2018).…”