3-nitrotyrosine and Niemann-Pick-Disease--Type-C

Niemann-Pick C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. We have previously reported that oxidative stress is the main upstream stimulus activating the proapoptotic c-Abl/p73 pathway in NPC neurons. We have also observed accumulation of vitamin E in NPC lysosomes, which could lead to a potential decrease of its bioavailability. Our aim was to determine if dietary vitamin E supplementation could improve NPC disease in mice. NPC mice received an alpha-tocopherol (α-TOH) supplemented diet and neurological symptoms, survival, Purkinje cell loss, α-TOH and nitrotyrosine levels, astrogliosis, and the c-Abl/p73 pathway functions were evaluated. In addition, the effect of α-TOH on the c-Abl/p73 pathway was evaluated in an in vitro NPC neuron model. The α-TOH rich diet delayed loss of weight, improved coordination and locomotor function and increased the survival of NPC mice. We found increased Purkinje neurons and α-TOH levels and reduced astrogliosis, nitrotyrosine and phosphorylated p73 in cerebellum. A decrease of c-Abl/p73 activation was also observed in the in vitro NPC neurons treated with α-TOH. In conclusion, our results show that vitamin E can delay neurodegeneration in NPC mice and suggest that its supplementation in the diet could be useful for the treatment of NPC patients.

Topics: alpha-Tocopherol; Animals; Caspase 3; Cell Line; Cell Survival; Dietary Supplements; Disease Models, Animal; DNA-Binding Proteins; Lysosomes; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Neurodegenerative Diseases; Niemann-Pick Disease, Type C; Nuclear Proteins; Oxidative Stress; Proto-Oncogene Proteins c-abl; Signal Transduction; Tumor Protein p73; Tumor Suppressor Proteins; Tyrosine; Vitamin E