Computational Insights into SPG50: Characterizing AP4M1 Mutations and Pioneering Drug Discovery Strategies

Spastic paraplegia type 50 (SPG50) is a neurodegenerative ultra-rare disease caused either by compound heterozygous or homozygous loss-of-function mutations in the AP4M1 gene.This gene encodes for the medium subunit of the adapter protein complex 4 (AP-4), which is involved in intracellular protein trafficking. As many other rare conditions, SPG50 is overlooked by pharmaceutical industries and no approved therapeutic treatments are available yet.In this work, a comprehensive computational approach was employed to investigate the consequences of SPG50-associated missense mutations at the protein level. The pipeline presented here includes the following steps: characterization of AP4M1 single residue variants, homology modelling of the AP-4 core, analysis of alternative AP-4 conformations, investigation of the binding of AP4M1 to cargo proteins, and evaluation of AP-4-membrane association events. The obtained results allowed to design a drug discovery strategy to target AP4M1 pathogenic variants.