Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Tau (MAPT) protein is a key driver of neuronal dysfunction in Alzheimer disease (AD) and other tauopathies.
• Understanding Tau's dynamic interactions is crucial for elucidating its role in neurodegeneration.

Purpose of the Study:

• To characterize Tau interactomes under conditions of neuronal activity and frontotemporal dementia (FTD) mutations.
• To identify Tau-binding proteins and map interaction sites within human induced pluripotent stem cell (iPSC)-derived neurons.

Main Methods:

• Utilized an engineered ascorbic acid peroxidase (APEX) proximity labeling approach.
• Employed quantitative affinity purification mass spectrometry (AP-MS) and proximity ligation assay (PLA).
• Investigated Tau interactions in iPSC-derived neurons with FTD-associated mutations and under stimulated neuronal activity.

Main Results:

• Identified Tau interactions with presynaptic vesicle proteins during activity-dependent Tau secretion.
• Mapped Tau-binding sites to cytosolic domains of synaptic vesicle proteins.
• Demonstrated that FTD mutations impair cellular bioenergetics and reduce Tau's interaction with mitochondrial proteins, which are downregulated in AD brains and correlate with disease severity.

Conclusions:

• Dynamic Tau interactomes reveal its role in synaptic function and neurodegenerative disease pathogenesis.
• FTD mutations impact Tau's interaction with mitochondria, linking bioenergetic deficits to Tau pathology.
• Identified potential therapeutic targets for blocking Tau-mediated neurodegeneration.