StARD9 Is a Multifunctional Kinesin That Couples LDL-Uptake to the Projection of Lysosomal Membrane Tubules

Niemann Pick Type C (NPC) disease is a rare pediatric neurodegenerative disorder that primarily impacts Purkinje cells in the cerebellum. The disease is an autosomal recessive disorder caused by point mutations on two cholesterol-binding proteins in the lysosome: NPC1 and NPC2. Live cell imaging of NPC1 mutations revealed a significant decrease in lysosomal tubulation, which is essential to cholesterol transport. StARD9 was recently identified as the kinesin that drives lysosomal tubulation. Similar to NPC disease cells, StARD9 depleted cells lack lysosomal tubulation and accumulate cholesterol. In addition, StARD9 knockout mice develop NPC disease symptoms.

Interestingly, StARD9 appears to be regulated by a proposed cholesterol-binding START domain at the C-terminus. Removal of this domain results in the loss of lysosomal tubulation, thereby causing a pathological accumulation of cholesterol within the lysosome. A novel lysosomal tubulation assay was generated to test StARD9 sterol-sensing in relation to lysosomal tubulation. Cells were starved of cholesterol and subjected to live cell imaging. Tubulation is significantly impaired in cholesterol-free conditions and is rescued by LDL treatment. This does not occur without StARD9 sterol-binding. Together, these results suggest that cholesterol acts a novel signaling molecule by binding to the START domain of StARD9 to stimulate lysosomal tubulation.

Oxysterols are natural cholesterol analogues that are known to modulate cholesterol metabolism. Interestingly, treatment with purified oxysterols also rescues lysosomal tubulation. One oxysterol, Oxysterol-X, was able to rescue lysosomal tubulation to control levels. Oxysterol-X treatment, through activation of lysosomal tubulation, ameliorated cholesterol accumulation in both in vitro and in vivo models of NPC disease.

Taken together, these studies demonstrate that StARD9 is a multifunctional kinesin that couples LDL-uptake to the projection of lysosomal membrane tubules, thereby serving as a compelling therapeutic target for treating NPC disease.