Cholesterol redistribution triggered by CYP46A1 gene therapy improves major hallmarks of Niemann-Pick type C disease but is not sufficient to halt neurodegeneration

Maria João Nunes, Andreia Neves Carvalho, Joana Reis, Daniela Costa, Miguel Moutinho, Joana Mateus, Rita Mendes de Almeida, Sara Brito, Daniela Risso, Sofia Nunes, Margarida Castro-Caldas, Maria João Gama, Cecília M.P. Rodrigues, Sara Xapelli, Maria José Diógenes, Nathalie Cartier, Farah Chali, Françoise Piguet, Elsa Rodrigues
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Abstract

Cholesterol 24-hydroxylase (CYP46A1) is an exclusively neuronal cytochrome P450 enzyme responsible for converting cholesterol into 24S-hydroxycholesterol, which serves as the primary pathway for eliminating cholesterol in the brain. We and others have shown that increased activity of CYP46A1 leads to reduced levels of cholesterol and has a positive effect on cognition. Therefore, we hypothesized that CYP46A1 could be a potential therapeutic target in Niemann-Pick type C (NPC) disease, a rare and fatal neurodegenerative disorder, characterized by cholesterol accumulation in endolysosomal compartments. Herein, we show that CYP46A1 ectopic expression, in cellular models of NPC and in Npc1tm(I1061T) mice by adeno-associated virus-mediated gene therapy improved NPC disease phenotype. Amelioration in functional, biochemical, molecular and neuropathological hallmarks of NPC disease were characterized. In vivo, CYP46A1 expression partially prevented weight loss and hepatomegaly, corrected the expression levels of genes involved in cholesterol homeostasis, and promoted a redistribution of brain cholesterol accumulated in late endosomes/lysosomes. Moreover, concomitant with the amelioration of cholesterol metabolism dysregulation, CYP46A1 attenuated microgliosis and lysosomal dysfunction in mouse cerebellum, favoring a pro-resolving phenotype. In vivo CYP46A1 ectopic expression improves important features of NPC disease and may represent a valid therapeutic approach to be used concomitantly with other drugs. However, promoting cholesterol redistribution does not appear to be enough to prevent Purkinje neuronal death in the cerebellum. This indicates that cholesterol buildup in neurons might not be the main cause of neurodegeneration in this human lipidosis.

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CYP46A1 基因疗法引发的胆固醇再分布改善了 C 型尼曼-皮克病的主要特征,但不足以阻止神经变性
胆固醇 24- 羟化酶(CYP46A1)是神经元特有的细胞色素 P450 酶,负责将胆固醇转化为 24S- 羟基胆固醇,这是消除大脑中胆固醇的主要途径。我们和其他人的研究表明,CYP46A1 活性的增加会导致胆固醇水平的降低,并对认知能力产生积极影响。因此,我们推测 CYP46A1 可能是治疗 C 型尼曼-皮克病(NPC)的潜在靶点。C 型尼曼-皮克病是一种罕见的致命性神经退行性疾病,其特征是胆固醇在溶酶体内腔积聚。在本文中,我们研究发现,通过腺相关病毒介导的基因疗法,CYP46A1在NPC细胞模型和Npc1tm(I1061T)小鼠中的异位表达改善了NPC疾病的表型。对鼻咽癌疾病的功能、生化、分子和神经病理学特征的改善是有特点的。在体内,CYP46A1的表达部分防止了体重减轻和肝肿大,纠正了参与胆固醇平衡的基因的表达水平,并促进了积聚在晚期内体/溶酶体中的脑胆固醇的重新分布。此外,在改善胆固醇代谢失调的同时,CYP46A1还减轻了小鼠小脑的小胶质细胞病变和溶酶体功能障碍,有利于形成有利于缓解的表型。体内 CYP46A1 异位表达可改善鼻咽癌疾病的重要特征,可能是与其他药物同时使用的有效治疗方法。然而,促进胆固醇重新分布似乎不足以防止小脑中普肯耶神经元的死亡。这表明,胆固醇在神经元中的积聚可能并不是这种人类脂质中毒症神经变性的主要原因。
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