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Therapeutic rescue of NPC phenotype by CYP46A1 cerebellar expression
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Niemann-Pick type C (NPC) disease is a rare neurogenerative disorder characterized by accumulation of cholesterol and other lipids in late endosomes/lysosomes. There are still limited therapeutic options available for NPC, but as it causes motor and intellectual impairment and premature death there is a high interest in the development of therapeutic strategies for this disease. CYP46A1 is a key enzyme involved in cholesterol homeostasis, which converts cholesterol to 24 (S)-hydroxycholesterol, being responsible for half of cholesterol turnover and the major brain cholesterol elimination pathway. Interestingly, increasing the expression or activity of the CYP46A1 resulted in beneficial effects in several animal models for neurodegenerative diseases. In this work, we aimed to study whether increased CYP46A1 expression would improve disease-associated biochemical alterations and disease phenotype in Npc1tm(I1061T) mice, that have a knock-in of the NPC1I1061T mutation, the most common mutation in NPC patients. For that, we used adeno-associated virus gene mediated therapy with a vector encoding CYP46A1, resulting in CYP46A1 ectopic expression.
Increased expression of CYP46A1 led to a positive increment in weight gain in female mice in later stages of the disease, nevertheless the same was not observed in males, probably because of the phenotypic heterogeneity observed between Npc1tm(I1061T) animals. CYP46A1 expression could not significantly prevent extensive Purkinje cell loss in the cerebellum, nor it ameliorated motor function, as assessed by the rotarod test and gait analysis. Nevertheless, molecular and biochemical analysis suggest that CYP46A1 ectopic expression is able to ameliorate important features of NPC disease, such as cholesterol homeostasis, lysosomal function and neuroinflammation. Indeed, CYP46A1 restores 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cathepsin D mRNA levels, together with reduction in the accumulation of lipidated microtubule-associated protein 1A/1B light chain 3B (LC3-II) indicating restoration of cholesterol homeostasis and improvement of the cellular intracellular traffic. Moreover, CYP46A1 expression could decrease astrogliosis and microgliosis in NPC male mice cerebellum. Overall, our promising results suggest that an earlier intervention, before the onset of the disease, can eventually open a new therapeutic avenue for this disease.
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Niemann-Pick type C (NPC) disease CYP46A1 cholesterol Purkinje cells neuroinflammation motor function