We screened 55 ER, lipid, mitochondrial, and trafficking-associated genes and found that siRNAs targeting HSP-causing ER-shaping proteins (including ATL1 and RTN2) result in the largest alterations in the ER network organisation, consistent with a central role for the disrupted ER organisation in the pathogenesis of HSP. Here, RTN2 is linked to hereditary spastic paraplegia.