AP-4: autophagy-four mislocalized proteins in axons

Neurons are highly polarized cells composed of two distinct domains, the axon and the somatodendritic domain. Although AMPA-type glutamate receptors, which mediate fast excitatory neurotransmission in the vertebrate CNS, are preferentially expressed in the somatodendritic domain, the molecular mechanisms underlying such polarized distribution have remained elusive. We recently demonstrated that adaptor protein complex-4 (AP-4) binds to transmembrane AMPA receptor regulatory proteins (TARPs), thereby mediating the selective trafficking of AMPA receptors to the somatodendritic domain; genetic disruption of AP-4 (AP-4beta(-/-)), results in the mislocalization of TARPs and AMPA receptors in the axons. Similarly, low-density lipoprotein receptors and delta2 glutamate receptors are mislocalized in axons, while other cargos, such as NMDA receptors and metabotropic glutamate receptors, are properly excluded from AP-4beta(-/-) axons. These findings indicate that there exist AP-4-dependent and -independent sorting mechanisms. Unexpectedly, mislocalized AMPA receptors do not reach the cell surface and accumulate in autophagosomes in the bulging portions of AP-4beta(-/-) axons. Several lines of evidence indicate that mislocalized AMPA receptors activate the autophagic pathway. Since increased autophagy and axonal swelling are suggested to occur in various neuronal disorders, further studies using AP-4beta(-/-) mice are warranted to understand the mechanisms regulating autophagy in axons.