LGALS4 and hereditary spastic paraplegia: To functionally validate the impact of CRL4 inhibition on spastin recovery and in reducing pathological defects associated with HSP in vivo, we could not use mouse models, because only SPG4-homozygous knockout mice lacking spastin protein exhibit neurological disease.34,35 Based on the phenotypes of spastin-loss-of function Drosophila models, which resemble the pathological defects of HSP in human,36-38 we exploited a model of SPG4 haploinsufficiency in Drosophila by employing the GAL4-UAS system39 to perform RNAi-mediated downregulation of spastin in different tissues.