Fig. 5

Hypothetical model describing the processes leading to HSP upon AMFR dysfunction. Upon loss of function of AMFR, degradation of HMGCR and INSIG proteins is likely blunted, resulting in an increased cholesterol synthesis rate upon HMGCR stabilization and a compensatory repression of SREBP processing causing reduced expression of lipogenic SREBP target genes upon stabilizing of INSIG proteins. The net effect of these opposing lipogenic and non-lipogenic processes is a disturbance in the balance of lipid and cholesterol homeostasis which is reflected by increased lipid droplet size in patient-derived fibroblasts and in human neural stem cells in the absence of AMFR. Possibly, cell-type-specific and species-specific differences in the balance between both opposite processes might occur, explaining the absence of increased cholesterol levels in patient serum and contradictory results in Amfr knockout mice. The increased lipid droplet size and concomitant alterations in the morphology of the endoplasmic reticulum then lead to neurotoxicity, causing dysfunction of the corticospinal tract due to an yet to be explored pathomechanism. Upon cholesterol lowering therapy in amfra-/- zebrafish larvae, this neurotoxicity is prevented, causing rescue of the observed phenotypes