Valenza M, Marullo M, Di Paolo E, Cesana E, Zuccato C, Biella G, Cattaneo E
Department of Biosciences and Centre for Stem Cell Research, Università degli Studi di Milano, Milano, Italy.
Department of Biology and Biotechnology, Università degli Studi di Pavia, Pavia, Italy.
Cell Death Differ. 2015 Apr;22(4):690-702. doi: 10.1038/cdd.2014.162. Epub 2014 Oct 10.
In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyte-neuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD.
在成人大脑中，神经元需要局部胆固醇生成，而这由星形胶质细胞通过含载脂蛋白E（apoE）的脂蛋白提供。在亨廷顿舞蹈症（HD）中，大脑中的这种胆固醇生物合成会严重减少。我们在此表明，星形胶质细胞中出现的这种缺陷对HD神经元有害。携带含有不断增加的CAG重复序列的亨廷顿蛋白的星形胶质细胞在培养基中分泌的与apoE脂蛋白结合的胆固醇较少。在神经突生长试验中，来自HD星形胶质细胞的条件培养基和来自野生型（wt）星形胶质细胞的脂蛋白耗尽的条件培养基同样有害，并且与胆固醇补充条件或来自wt星形胶质细胞的条件培养基相比，不支持HD神经元的突触活动。星形胶质细胞中胆固醇生物合成和流出的分子扰动导致类似的星形胶质细胞 - 神经元相互作用改变，而增强胶质细胞的固醇调节元件结合蛋白2（SREBP2）和ATP结合盒转运体A1（ABCA1）功能可逆转HD中神经元功能障碍的各个方面。这些发现表明，星形胶质细胞介导的胆固醇稳态可能是改善HD中神经元功能障碍的潜在治疗靶点。
