Axon Trafficking Counteracts Aberrant Protein Aggregation in Neurons

Directed axon trafficking of mRNA via ribonucleoprotein complexes (RNPs) is essential for the proper function and survival of neurons. However, the mechanisms governing RNP transport in axons remain poorly understood. Here, we identify Annexin A7 (ANXA7) as a critical adaptor facilitating the retrograde transport of T-cell intracellular antigen 1 (TIA1)-containing RNPs by linking them to the cytoplasmic dynein. Persistent axonal Ca{superscript 2} elevation disrupts ANXA7s linker role, causing the detachment of TIA1 granules from dynein, consequently impairing transport and triggering pathological TIA1 aggregation within axons. Similarly, ANXA7 knockdown decouples TIA1 granules from dynein, severely obstructing trafficking and causing pathological aggregation of TIA1 in axons, which culminates in axonopathy and neurodegeneration both in vitro and in vivo. Conversely, ANXA7 overexpression enhances trafficking and counteracts aberrant aggregation of TIA1-containing RNPs in axons. Our findings elucidate a novel mechanism underlying RNP axonal transport, highlighting its significance in the biology and pathology of central neurons.