Syntaxins 6 and 8 facilitate tau into secretory pathways

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Tau pathology is a hallmark of Alzheimer's disease (AD) and other tauopathies, characterized by its spread through neuronal connections.
• The molecular mechanisms driving tau release from cells, a prerequisite for pathology propagation, were previously unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms responsible for tau release from cells.
• To identify proteins that mediate the intercellular spread of tau pathology in neurodegenerative diseases.

Main Methods:

• Established the interactome of the C-terminal tau region to identify interacting proteins.
• Investigated the role of identified syntaxins (STX6, STX8) in mediating tau release using cell-based assays.
• Determined the functional domains of syntaxins involved in tau secretion.

Main Results:

• Identified syntaxin 8 (STX8) as a mediator of tau release from cells.
• Demonstrated that syntaxin 6 (STX6), also a SNARE family member, facilitates tau release.
• Showed that the transmembrane domain of STX6 is essential and sufficient for mediating tau secretion.
• Highlighted potential differential roles of STX6 and STX8 in distinct secretory pathways.

Conclusions:

• Syntaxins STX6 and STX8 are critical mediators of tau release, suggesting their involvement in the spread of tau pathology in AD and PSP.
• Targeting these syntaxin-mediated pathways could offer novel therapeutic strategies for tauopathies.