Figure 1: Schematic illustration of impaired lipid homeostasis in SPG3A. In astrocytes derived from SPG3A human pluripotent stem cells (left panel), ATL1 mutations result in LD defects and impaired cholesterol trafficking (reduced NR1H2, APOE, and efflux), leading to cholesterol deficiency and axonal degeneration in SPG3A cortical PNs. The application of GW3965, a NR1H2 agonist, mitigates the LD and lipid metabolism defects in SPG3A astrocytes, and promotes cholesterol efflux from SPG3A astrocytes (Mou et al., 2020). Subsequently, the cholesterol deficiency and axonal degeneration in SPG3A cortical PNs (right panel) were rescued, revealing a non-cell autonomous role of astrocytes in axonal degeneration of SPG3A cortical neurons. APOE: Apolipoprotein E; LD: lipid droplet; NR1H2: nuclear receptor subfamily 1 group H member 2; PLIN2: perilipin 2; PLIN3: perilipin 3.