Mack Jody T, Beljanski Vladimir, Soulika Athena M, Townsend Danyelle M, Brown Carol B, Davis Warren, Tew Kenneth D
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, P.O. Box 250505, Charleston, SC 29425, USA.
Mol Cell Biol. 2007 Jan;27(1):44-53. doi: 10.1128/MCB.01824-06. Epub 2006 Oct 23.
The ATP-binding cassette transporter 2 (ABCA2) is an endolysosomal protein most highly expressed in the central and peripheral nervous system tissues and macrophages. Previous studies indicated its role in cholesterol/steroid (estramustine, estradiol, and progesterone) trafficking/sequestration, oxidative stress response, and Alzheimer's disease. Developmental studies have shown its expression during macrophage and oligodendrocyte differentiation, processes requiring membrane growth. To determine the in vivo function(s) of this transporter, we generated a knockout mouse from a gene-targeted disruption of the murine ABCA2 gene. Knockout males and females are viable and fertile. However, a non-Mendelian inheritance pattern was shown among male progeny of heterozygous crosses. Compared to wild-type and heterozygous littermates, knockout mice displayed a tremor without ataxia, hyperactivity, and reduced body weight; the latter two phenotypes were more marked in females than in males. This sexual disparity suggests a role for ABCA2 in hormone-dependent neurological and/or developmental pathways. Myelin sheath thickness in the spinal cords of knockout mice was greatly increased compared to that in wild-type mice, while a significant reduction in myelin membrane periodicity (compaction) was observed in both spinal cords and cerebra of knockout mice. Loss of ABCA2 function in vivo resulted in abnormal myelin compaction in spinal cord and cerebrum, an ultrastructural defect that we propose to be the cause of the phenotypic tremor.
ATP结合盒转运蛋白2（ABCA2）是一种主要在中枢和外周神经系统组织以及巨噬细胞中高度表达的溶酶体蛋白。先前的研究表明其在胆固醇/类固醇（雌莫司汀、雌二醇和孕酮）转运/隔离、氧化应激反应以及阿尔茨海默病中发挥作用。发育研究显示其在巨噬细胞和少突胶质细胞分化过程中表达，而这些过程需要膜生长。为了确定该转运蛋白的体内功能，我们通过对小鼠ABCA2基因进行基因靶向破坏构建了敲除小鼠。敲除的雄性和雌性小鼠均存活且可育。然而，在杂合子杂交的雄性后代中显示出非孟德尔遗传模式。与野生型和杂合子同窝小鼠相比，敲除小鼠表现出无共济失调的震颤、多动以及体重减轻；后两种表型在雌性中比在雄性中更为明显。这种性别差异表明ABCA2在激素依赖性神经和/或发育途径中发挥作用。与野生型小鼠相比，敲除小鼠脊髓中的髓鞘厚度大大增加，而在敲除小鼠的脊髓和大脑中均观察到髓鞘膜周期性（紧密程度）显著降低。体内ABCA2功能丧失导致脊髓和大脑中的髓鞘紧密程度异常，我们认为这种超微结构缺陷是表型震颤的原因。
