Adaptor protein complex 4 subunit epsilon 1 (AP4E1) (AP4E1)

Adaptor protein complex 4 subunit epsilon 1 (AP4E1) is a critical component of the heterotetrameric AP-4 complex, which facilitates the sorting and transport of cargo proteins from the trans-Golgi network to the endosomal-lysosomal system (UniProt P48059). A primary cargo for this complex is ATG9A, an essential protein for the initiation of autophagy, particularly in neurons (PMID: 25533962). Loss-of-function mutations in AP4E1 result in AP-4-associated hereditary spastic paraplegia, specifically the SPG51 subtype, which is characterized by early-onset spasticity, intellectual disability, and microcephaly (OMIM 607244). The disease mechanism involves the mislocalization of ATG9A, leading to impaired autophagy and axonal degeneration (PMID: 22020113). Currently, AP4E1 is a target for experimental gene therapies designed to restore the functional AP-4 complex and normalize intracellular trafficking. There are no approved small-molecule drugs for this target, but research into stabilizing the complex or bypassing the trafficking defect is ongoing. The complex is also being studied for its role in other neurodevelopmental pathways and its potential as a biomarker for autophagic flux in the central nervous system.

Other names

AP-4 complex subunit epsilon-1Adaptor-related protein complex 4 subunit epsilon-1SPG51CPSQ1Epsilon-adaptor

Restoration of protein trafficking and autophagy through gene replacement or stabilization of the AP-4 complex (PMID: 31619608).