Proteomic Characterization of the Alzheimer's Disease Risk Factor BIN1 Interactome

Area of Science:

• Neuroscience
• Genetics
• Proteomics

Background:

• BIN1 is a major genetic risk factor for late-onset Alzheimer's disease (LOAD).
• Neuronal BIN1 regulates presynaptic function, but its interacting partners and precise role in LOAD remain unclear.
• Characterizing neuronal BIN1 interactors is crucial for understanding its function in the brain.

Purpose of the Study:

• To identify and characterize neuronal BIN1-interacting and proximal proteins.
• To uncover novel BIN1 functions in neurons relevant to LOAD pathogenesis.
• To establish a foundation for future research on neuronal BIN1.

Main Methods:

• Utilized TurboID-based proximity labeling with a neuronal BIN1 isoform 1-TurboID fusion protein (BIN1iso1-TID).
• Performed label-free quantification proteomics in cultured N2a cells and adult mouse brain neurons.
• Validated identified interactors using immunostaining and proximity ligation assays.

Main Results:

• Identified 360 proteins in N2a cells and 897 proteins in mouse brain neurons associated with BIN1iso1-TID.
• Discovered 92 high-confidence common BIN1-interacting or proximity proteins across both datasets.
• SynapticGO analysis revealed 159 labeled synaptic proteins, including 60 involved in the synaptic vesicle cycle.
• Validated AAK1, CDK16, SYNJ1, PP2BA, and RANG as BIN1 interactors in the mouse brain.

Conclusions:

• This study provides a comprehensive map of neuronal BIN1 interactors and proximal proteins.
• Identified novel synaptic proteins associated with BIN1, highlighting its role in synaptic vesicle cycling.
• The findings lay the groundwork for elucidating the specific functions of neuronal BIN1 in Alzheimer's disease.