Abstract
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.
Highlights
Niemann-Pick type C (NPC) is an inherited progressive neurovisceral disease [1,2]. This genetic disease is caused by the mutation of one of the genes encoding for the NPC1 or NPC2 proteins [2,3,4,5], which are involved in the transport of free cholesterol from the endosomal/lysosomal compartment to the rest of the cell
A decrease of c-Abl/p73 activation was observed in in vitro NPC neurons treated with α-TOH. Together these 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
In order to test the effect of the vitamin E treatment, wild-type and NPC mice were fed with an α-TOH supplemented diet (2000 IU/Kg DL-Alpha Tocopherol Acetate) and a control diet starting at p28
Summary
Niemann-Pick type C (NPC) is an inherited progressive neurovisceral disease [1,2]. This genetic disease is caused by the mutation of one of the genes encoding for the NPC1 or NPC2 proteins [2,3,4,5], which are involved in the transport of free cholesterol from the endosomal/lysosomal compartment to the rest of the cell. Mutations in the Npc gene (95% of NPC cases) and in the Npc gene (5% of NPC cases) produce the same phenotype leading to accumulation of unesterified cholesterol and other lipids within lysosomes [2,8]. One of the hallmarks of NPC disease is a progressive and extensive neurodegeneration which is caused by an increase in apoptosis [9]. There is a general loss of neurons in the Central Nervous System (CNS), cerebellar Purkinje cells are early and especially affected [1,10,11,12,13,14]
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