Dissecting the role of cytoplasmic signaling metabolites in Niemann-Pick disease type C

Niemann-Pick type C disease (NPCD) is a genetic disease caused by mutations in the NPC1 gene. NPCD manifests with a broad spectrum of neurological symptoms, including motor and cognitive impairment, psychiatric disturbances that progressively degenerate to cause premature death. Neurological decline is linked to the fact that neurons cannot function properly, and ultimately die. Failing neurons accumulate cholesterol within tiny intracellular structures, called lysosomes that are widely known as the cell's "waste disposal" for their role in recycling of exhausted proteins. But why disorder in lysosomal storage leads to neurodegeneration is largely unknown.

Lysosomes are also structures able to sense nutritional inputs; cholesterol overload caused by NPC1 mutations fools the cell that activates downstream mechanisms, most notably the master regulator of cell growth: mTORC1. We hypothesize that aberrant activation of mTORC1 leads to cellular malfunctioning through impact on a specific metabolic axis that centers around the mevalonate pathway.

To tackle our hypothesis, we will examine how nutrients are utilized by NPCD or normal neurons. As glucose catabolism feeds the mevalonate pathway, we anticipate a significant rewiring of its utilization, which can be mapped using mass spectrometry-based approaches. The effect of mTORC1 inhibition will also be assessed. We will next supplement NPCD cells with exogenous metabolites of the mevalonate pathway that are suppressed by NPC1 deficiency and test their ability to restore neuronal fitness. Finally, we will examine how the building block of the mevalonate pathway, a metabolite termed acetyl-CoA, influences genomic architecture and plasticity of neuronal cells.