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(American Journal of Pathology. 2005;167:1081-1092.)
© 2005 American Society for Investigative Pathology

Deregulation of the Phosphatidylinositol-3 Kinase Signaling Cascade Is Associated with Neurodegeneration in Npc1–/– Mouse Brain

Xiaoning Bi^*, Jihua Liu^*, Yueqin Yao^*, Michel Baudry and Gary Lynch^*

From the Department of Psychiatry and Human Behavior,^* University of California at Irvine, Irvine; and Neurobiology, University of Southern California, Los Angeles, California

Niemann-Pick type C (NPC) disease is caused by mutations to genes that encode proteins critical to intracellular lipid homeostasis. The events underlying NPC progressive neurodegeneration are poorly understood but include neurofibrillary tangles of the type found in Alzheimer’s disease. Here we investigated possible contributions of a phosphatidylinositol-3 kinase cascade [PI3K, Akt, glycogen synthase kinase-3ß (GSK-3ß)] that is linked to apoptosis and various degenerative conditions. Brain concentrations of phosphorylated Akt, which phosphorylates and inactivates GSK-3ß, were significantly elevated in Npc1–/– mice relative to Npc1+/+ mice. Accordingly, levels of inactive GSK-3ß were 50 to 100% higher in mutant brains than in controls. Increases in inactive GSK-3ß occurred early in postnatal development, well before neuronal loss, and were most prominent in structures with intracellular cholesterol accumulation, suggesting a contribution to subsequent degeneration. Perturbations of nuclear factor (NF)-B, which is regulated by GSK-3ß, occurred in Npc1–/– mouse brains. Nuclear concentrations and DNA binding activity of NF-B’s transactivation subunit, p65, were significantly reduced in Npc1–/– mice compared to Npc1+/+ mice. Cytoplasmic levels of the p50 subunit and its precursor, p105, were higher in Npc1–/– mice. These results suggest that excessive activity in the PI3K-Akt pathway depresses GSK-3ß, thereby disrupting the formation and/or nuclear import of p50/p65 NF-B dimers and contributing to neuronal degeneration.

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