Louis Sam Titus Anto Sam Crosslee, Yusuff Tanzeen, Cassar Marlène, Thomas Elizabeth, Kretzschmar Doris, D'Mello Santosh R
Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, Texas 75080.
Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275.
J Neurosci. 2017 Jul 5;37(27):6575-6587. doi: 10.1523/JNEUROSCI.3612-16.2017. Epub 2017 May 26.
Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine expansion in the huntington protein (). The neuropathological hallmark of HD is the loss of neurons in the striatum and, to a lesser extent, in the cortex. is a member of the Forkhead family of transcription factors expressed selectively in the striatum and the cortex. In the brain, three major isoforms are expressed: isoform-A (∼90 kDa), isoform-D (∼70 kDa), and isoform-C (∼50 kDa). We find that expression of isoform-A and -D is selectively reduced in the striatum and cortex of R6/2 HD mice as well as in the striatum of HD patients. Furthermore, expression of mutant in neurons results in the downregulation of Elevating expression of isoform-A or -D protects cortical neurons from death caused by the expression of mutant On the other hand, knockdown of promotes death in otherwise healthy neurons. Neuroprotection by is likely to be mediated by the transcriptional stimulation of the cell-cycle inhibitory protein Consistently, activates transcription of the gene promoter, and overexpression of in neurons results in the elevation of p21 expression. Moreover, knocking down of blocks the ability of to protect neurons from mut--induced neurotoxicity. We propose that the selective vulnerability of neurons of the striatum and cortex in HD is related to the loss of expression of , a protein that is highly expressed in these neurons and required for their survival. Although the mutant huntingtin gene is expressed widely, neurons of the striatum and cortex are selectively affected in Huntington's disease (HD). Our results suggest that this selectivity is attributable to the reduced expression of Foxp1, a protein expressed selectively in striatal and cortical neurons that plays a neuroprotective role in these cells. We show that protection by involves stimulation of the () gene. Although three major isoforms (A, C, and D) are expressed in the brain, only isoform-A has been studied in the nervous system. We show that isoform-D is also expressed selectively, neuroprotective and downregulated in HD mice and patients. Our results suggest that might be an attractive therapeutic target for HD.
亨廷顿舞蹈症（HD）是一种遗传性神经退行性疾病，由亨廷顿蛋白中的多聚谷氨酰胺扩增引起。HD的神经病理学标志是纹状体神经元的丧失，在较小程度上还有皮质神经元的丧失。[此处原文缺失相关蛋白名称]是在纹状体和皮质中选择性表达的叉头转录因子家族的成员。在大脑中，表达三种主要的[此处原文缺失相关蛋白名称]异构体：异构体A（约90 kDa）、异构体D（约70 kDa）和异构体C（约50 kDa）。我们发现，异构体A和D在R6/2 HD小鼠的纹状体和皮质以及HD患者的纹状体中表达选择性降低。此外，神经元中突变型[此处原文缺失相关蛋白名称]的表达导致[此处原文缺失相关蛋白名称]的下调。提高异构体A或D的表达可保护皮质神经元免受突变型[此处原文缺失相关蛋白名称]表达引起的死亡。另一方面，敲低[此处原文缺失相关蛋白名称]会促进原本健康的神经元死亡。[此处原文缺失相关蛋白名称]的神经保护作用可能是通过细胞周期抑制蛋白[此处原文缺失相关蛋白名称]的转录刺激介导的。一致地，[此处原文缺失相关蛋白名称]激活[此处原文缺失相关基因名称]基因启动子的转录，并且神经元中[此处原文缺失相关蛋白名称]的过表达导致p21表达升高。此外，敲低[此处原文缺失相关蛋白名称]会阻断[此处原文缺失相关蛋白名称]保护神经元免受突变型[此处原文缺失相关蛋白名称]诱导的神经毒性的能力。我们提出，HD中纹状体和皮质神经元的选择性易损性与[此处原文缺失相关蛋白名称]表达的丧失有关，[此处原文缺失相关蛋白名称]是一种在这些神经元中高度表达且对其存活至关重要的蛋白质。尽管突变的亨廷顿基因广泛表达，但纹状体和皮质神经元在亨廷顿舞蹈症（HD）中受到选择性影响。我们的结果表明，这种选择性归因于Foxp1表达的降低，Foxp1是一种在纹状体和皮质神经元中选择性表达且在这些细胞中起神经保护作用的蛋白质。我们表明，[此处原文缺失相关蛋白名称]的保护作用涉及对[此处原文缺失相关基因名称]（[此处原文缺失相关基因名称]）基因的刺激。尽管大脑中表达三种主要的[此处原文缺失相关蛋白名称]异构体（A、C和D），但在神经系统中仅研究了异构体A。我们表明，异构体D在HD小鼠和患者中也选择性表达、具有神经保护作用且表达下调。我们的结果表明，[此处原文缺失相关蛋白名称]可能是HD的一个有吸引力的治疗靶点。
