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.

This study was supported by grants from the Fondo Nacional de Desarrollo Científico y/nTecnológico (FONDECYT) (grant numbers 1120512 to A.R.A, and 1110310 to S.Z); Fondo de/nFomento al Desarrollo Científico y Tecnológico FONDEF D10I1077 (to A.R.A and S.Z.);/nFondo Nacional de Desarrollo de Areas Prioritarias, FONDAP, Project no. 15090007, Center for/nGenome Regulation (CGR) to S.Z.; Generalitat de Catalunya (SGR2009-1369) and La Marató de TV3/n(No. 100310)