Leoni Valerio, Caccia Claudio
Laboratory of Clinical Chemistry, Ospedale Causa Pia Luvini, Cittiglio, AO Ospedale di Circolo e Fondazione Macchi, Varese, Italy; Laboratory of Clinical Pathology and Medical Genetics, Foundation IRCCS Institute of Neurology Carlo Besta, Milano, Italy.
Laboratory of Clinical Pathology and Medical Genetics, Foundation IRCCS Institute of Neurology Carlo Besta, Milano, Italy.
Biochim Biophys Acta. 2015 Aug;1851(8):1095-105. doi: 10.1016/j.bbalip.2014.12.018. Epub 2015 Jan 14.
Huntington disease (HD), an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of CAG trinucleotide repeat in the Huntingtin (HTT) gene, is characterized by extensive neurodegeneration of striatum and cortex and severe diffuse atrophy at MRI. The expression of genes involved in the cholesterol biosynthetic pathway and the amount of cholesterol, lanosterol, lathosterol and 24S-hydroxycholesterol were reduced in murine models of HD. In case of HD-patients, the decrease of plasma 24OHC follows disease progression proportionally to motor and neuropsychiatric dysfunction and MRI brain atrophy, together with lanosterol and lathosterol (markers of cholesterol synthesis), and 27-hydroxycholesterol. A significant reduction of total plasma cholesterol was observed only in advanced stages. It is likely that mutant HTT decreases the maturation of SREBP and the up-regulation LXR and LXR-targeted genes (SREBP, ABCG1 and ABCG4, HMGCoA reductase, ApoE) resulting into a lower synthesis and transport of cholesterol from astrocytes to neurons via ApoE. In primary oligodendrocytes, mutant HTT inhibited the regulatory effect of PGC1α on cholesterol metabolism and on the expression of MBP. HTT seems to play a regulatory role in lipid metabolism. The impairment of the cholesterol metabolism was found to be proportional to the CAG repeat length and to the load of mutant HTT. A dysregulation on PGC1α and mitochondria dysfunction may be involved in an overall reduction of acetyl-CoA and ATP synthesis, contributing to the cerebral and whole body cholesterol impairment. This article is part of a Special Issue entitled Brain Lipids.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，由亨廷顿（HTT）基因中CAG三核苷酸重复序列异常扩增引起，其特征为纹状体和皮质广泛神经变性，以及MRI显示的严重弥漫性萎缩。在HD小鼠模型中，参与胆固醇生物合成途径的基因表达以及胆固醇、羊毛甾醇、羊毛固醇和24S - 羟基胆固醇的含量均降低。对于HD患者，血浆24OHC的降低与疾病进展成比例，与运动和神经精神功能障碍以及MRI脑萎缩、羊毛甾醇和羊毛固醇（胆固醇合成标志物）以及27 - 羟基胆固醇相关。仅在疾病晚期观察到总血浆胆固醇显著降低。突变型HTT可能会降低固醇调节元件结合蛋白（SREBP）的成熟以及肝X受体（LXR）和LXR靶向基因（SREBP、ABCG1和ABCG4、3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶、载脂蛋白E）的上调，导致通过载脂蛋白E从星形胶质细胞向神经元的胆固醇合成和转运降低。在原代少突胶质细胞中，突变型HTT抑制了过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）对胆固醇代谢和髓鞘碱性蛋白（MBP）表达的调节作用。HTT似乎在脂质代谢中起调节作用。发现胆固醇代谢受损与CAG重复长度和突变型HTT的负荷成比例。PGC1α失调和线粒体功能障碍可能参与乙酰辅酶A和ATP合成的整体降低，导致脑和全身胆固醇受损。本文是名为“脑脂质”的特刊的一部分。
