Remarkably, around half of AD-HSP patients carry mutations affecting proteins that have a direct role in ER shaping (e.g., Atlastin-1, Reticulon-2, or REEP1) or act on cellular pathways that indirectly have an impact on ER tubules shape or positioning (e.g., cytoskeleton maintenance, ER-phagy, ER stress) (Figure 1 and Table 1). The gene discussed is REEP1; the disease is hereditary spastic paraplegia.