Bryan Miles R, Bowman Aaron B
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
Adv Neurobiol. 2017;18:113-142. doi: 10.1007/978-3-319-60189-2_6.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival. Manganese (Mn) is an essential metal to all biological systems but, in excess, can be toxic. Interestingly, several studies have revealed the insulin-mimetic effects of Mn-demonstrating Mn can activate several of the same metabolic kinases and increase peripheral and neuronal insulin and IGF-1 levels in rodent models. Separate studies have shown mouse and human striatal neuroprogenitor cell (NPC) models exhibit a deficit in cellular Mn uptake, indicative of a Mn deficiency. Furthermore, evidence from the literature reveals a striking overlap between cellular consequences of Mn deficiency (i.e., impaired function of Mn-dependent enzymes) and known HD endophenotypes including excitotoxicity, increased reactive oxygen species (ROS) accumulation, and decreased mitochondrial function. Here we review published evidence supporting a hypothesis that (1) the potent effect of IGF or insulin treatment on HD models, (2) the insulin-mimetic effects of Mn, and (3) the newly discovered Mn-dependent perturbations in HD may all be functionally related. Together, this review will present the intriguing possibility that intricate regulatory cross-talk exists between Mn biology and/or toxicology and the insulin/IGF signaling pathways which may be deeply connected to HD pathology and, perhaps, other neurodegenerative diseases (NDDs) and other neuropathological conditions.
亨廷顿舞蹈症（HD）是一种常染色体显性神经退行性疾病，可导致患者出现运动障碍并最终死亡。最近，多项研究表明，在HD模型中进行胰岛素或胰岛素样生长因子（IGF）治疗，可通过调节PI3K/AKT/mTOR信号通路有效改善HD表型。给予IGF和胰岛素可挽救微管运输、代谢功能和自噬缺陷，从而清除亨廷顿蛋白（HTT）聚集体、恢复线粒体功能、改善运动异常并提高生存率。锰（Mn）是所有生物系统必需的金属，但过量时可能有毒。有趣的是，多项研究揭示了Mn的胰岛素模拟作用——表明Mn可激活几种相同的代谢激酶，并提高啮齿动物模型外周和神经元胰岛素及IGF-1水平。另外的研究表明，小鼠和人类纹状体神经祖细胞（NPC）模型存在细胞Mn摄取缺陷，提示Mn缺乏。此外，文献证据显示，Mn缺乏的细胞后果（即Mn依赖性酶功能受损）与已知的HD内表型之间存在显著重叠，包括兴奋毒性、活性氧（ROS）积累增加和线粒体功能下降。在此，我们综述已发表的证据，以支持以下假设：（1）IGF或胰岛素治疗对HD模型具有显著效果；（2）Mn具有胰岛素模拟作用；（3）新发现的HD中Mn依赖性扰动可能在功能上都相关。总之，本综述将提出一种有趣的可能性，即Mn生物学和/或毒理学与胰岛素/IGF信号通路之间存在复杂的调节性相互作用，这可能与HD病理学以及其他神经退行性疾病（NDD）和其他神经病理状况密切相关。
