Abstract
Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC) disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) and murine double minute (Mdm2) E3 ligase. Growth cone collapse induced by genetic (npc1−/−) or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK)-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1−/− mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism.
Highlights
Axonal degeneration is a common feature of many neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis, Parkinson’s disease, and Niemann-Pick type C (NPC) disease
In the present study we report that disruption of cholesterol egress from late endosomes/lysosomes induced by NPC1 deficiency or pharmacological manipulation resulted in growth cone collapse that was associated with abnormal activation of p38 mitogenactivated protein kinase (MAPK), which in turn led to Mdm2dependent p53 degradation
Hippocampal neurons from embryonic day 18 (E18) npc12/2 and npc1+/+ embryos were cultured for 4 days in vitro (DIV) and processed for doubleimmunofluorescent staining with antibodies against E6-AP, an E3 ligase, and phosphorylated p53; both proteins were highly expressed in axons and growth cones, as previously reported [17]
Summary
Axonal degeneration is a common feature of many neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis, Parkinson’s disease, and Niemann-Pick type C (NPC) disease. NPC disease is caused by mutations in NPC1 or NPC2 gene, with late endosomal/lysosomal cholesterol accumulation as its characteristic pathologic feature. Neuronal degeneration as well as other neuropathological features, including abnormal formation of meganeurites (spindle-shaped swelling in the initial segments of axons) and axonal spheroids, and inflammation have been reproduced in murine models of the disease [3,4,5,6]. NPC pathology shares several features with AD pathology, including neurofibrillary tangles, autophagic/lysosomal dysfunction, inflammation, and cholesterol metabolism abnormalities [7,8,9,10]. NPC has often been used as a model system to study AD pathology
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