Our group explores tissue-specific proteostasis with a focus on NPC1 proteostasis in liver and brain, the two organs most affected in Niemann-Pick type C disease. Our investigations seek to identify whether tissue-specific therapeutics may be required to combat Niemann-Pick type C disease symptom progression.
Glycosylation
Glycans are topological regulators of protein folding, trafficking, and function. NPC1 is a heavily glycosylated protein however, little is known about how glyans impact NPC1 folding, trafficking, and degradation. As we have seen comparing mouse and human NPC1, differential glycosylation can drive differential protein trafficking and therapeutic response.
Degradation Pathways
Our group was the first to report that I1061T-NPC1, the most common disease variant, is degraded by both MARCH6-dependent ERAD as well as FAM134B-dependent ER-phagy. Interestingly, FAM134B exists in multiple forms with different forms being predominant in hepatocytes compared to neurons. This observation provides further opportunities to explore tissue-specific degradation pathways. In order to address these questions, we have optimized protocols for differentiating iPSCs into both neurons and hepatic progenitor cells.