Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to spastic paraplegia (HSP), leads to a similar build of lysosomes in structures we term “AP-4 dystrophies.” Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, β-site cleaving enzyme 1 (BACE1) and Presenilin 2. Here, BACE1 is linked to Spastic paraplegia.