Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau.

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Synaptic dysfunction is an early hallmark of Tau-associated neurodegenerative diseases like Alzheimer's disease (AD).
• Understanding the mechanisms of Tau-induced synaptic defects is crucial for developing effective therapies to prevent cognitive decline.
• Tau protein mislocalization into pre- and postsynaptic compartments is observed in disease conditions.

Purpose of the Study:

• To investigate the molecular mechanisms underlying Tau's role in synaptic dysfunction.
• To identify specific binding partners of Tau on synaptic vesicles in pathological conditions.
• To explore the therapeutic potential of targeting Tau-synaptic vesicle interactions.

Main Methods:

• Analysis of Alzheimer's disease patient brain tissue to detect Tau binding to synaptic vesicles.
• Identification of the transmembrane protein Synaptogyrin-3 as the mediator of Tau-synaptic vesicle binding.
• Utilizing fly and mouse models of Tauopathy to assess the functional impact of Synaptogyrin-3 reduction.

Main Results:

• Tau was shown to bind to presynaptic vesicles in Alzheimer's disease patient brains under pathological conditions.
• Synaptogyrin-3 was identified as the specific binding partner mediating the interaction between Tau and synaptic vesicles.
• Reduction of Synaptogyrin-3 in Tauopathy models prevented presynaptic Tau-vesicle association, improved vesicle mobility, and restored neurotransmitter release.

Conclusions:

• Synaptogyrin-3 is a novel presynapse-specific interactor of Tau on synaptic vesicles.
• Targeting the Tau-Synaptogyrin-3 interaction may represent a promising therapeutic strategy for early synaptic dysfunction in Tauopathies.
• This finding provides new insights into the pathogenesis of synaptic failure in neurodegenerative diseases associated with Tau.