Niemann-Pick Type C Disease: Molecular Mechanisms of Neurodegeneration and Targets for Therapeutic Intervention.

Abstract

Niemann-Pick Type C disease (NPC) is a childhood-onset neurodegenerative disorder characterized by the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes. Most NPC cases are caused by loss-of-function mutations in the ubiquitously expressed NPC1 gene, which encodes a multi-pass transmembrane protein essential for mobilizing cholesterol from the endolysosomal system. How NPC1 dysfunction leads to progressive neurodegeneration remains unknown and effective treatment is lacking. I used a conditional knockout mouse model of NPC to define the timing and cell type underlying neurodegeneration due to Npc1 deficiency. Global deletion of Npc1 in adult mice leads to progressive weight loss, impaired motor function and early death similar to that resulting from germline deletion. Additionally, the disease can be recapitulated when Npc1 is specifically deleted in neurons. In contrast, Npc1 deficiency in mature astrocytes does not produce any detectable defects. These findings demonstrate that neurons, but not astrocytes, play a critical role in the pathogenesis of NPC. I also explored the contribution of exogenously derived cholesterol to CNS myelination. I showed that Npc1 deficiency in either neurons or oligodendrocytes is sufficient to block oligodendrocyte maturation and myelination, with the most severe impairment in the forebrain. In addition, Npc1 deficiency in oligodendrocytes also leads to demyelination and secondary Purkinje neuron degeneration in aged mice. These data demonstrate that lipid uptake by neurons and oligodendrocytes through an Npc1-dependent pathway is required for both the formation and maintenance of CNS myelin. In addition, I explored a potential treatment strategy that targets mutant NPC1 protein with missense mutations. My data demonstrate that by increasing ER calcium levels in patient fibroblasts, ryanodine receptor antagonists increase the steady-state levels of the NPC1 I1061T protein, promote its trafficking to the late endosomes and lysosomes, and recue the lipid storage defects. My work highlights the utility of proteostasis regulators to remodel the ER protein folding environment to enable functional recovery. In summary, the findings presented here provide new insights into the pathogenic mechanisms underlying NPC and suggest a possible approach for therapeutic intervention.