The Use of Perinatal 6-Hydroxydopamine to Produce a Rodent Model of Lesch-Nyhan Disease.
The Use of Perinatal 6-Hydroxydopamine to Produce a Rodent Model of Lesch-Nyhan Disease.
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使用围产期 6-羟基多巴胺制作 Lesch-Nyhan 病啮齿动物模型。
DOI：
10.1007/7854_2016_444
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发表时间：
2016
影响因子：
--
通讯作者：
G. Breese
中科院分区：
文献类型：
--
作者：
D. Knapp;G. Breese
Lesch-Nyhan病是一种神经学、代谢和行为上的破坏性疾病，一直无法完全表征和充分治疗。虽然已知该疾病与编码嘌呤代谢酶（次黄嘌呤-鸟嘌呤磷酸核糖基转移酶）的次黄嘌呤磷酸核糖基转移酶1（HPRT 1）基因的功能障碍密切相关，并且与神经、行为以及代谢功能障碍相关，但神经行为表现的机制尚不清楚。然而，过去几十年的发现不仅创造了有用的新型动物模型（例如，HPRT缺陷小鼠和意外发现的围产期6-羟基多巴胺（6-OHDA损伤模型），而且还扩展到表观遗传学，基因组学和蛋白质组学方法，以更好地了解这种疾病的机制。围产期6-OHDA模型，除了在临床条件下模拟自伤和多巴胺耗竭外，还强调了在不同年龄面临共同/单一神经毒性损伤时，适应不良进展的不同过程中发育的重要性。临床和基础科学研究的最新进展证明，虽然这种疾病的核心似乎是一个简单的单基因缺陷，但这种缺陷的表现是深刻的，而且出乎意料地多样化。未来的努力采用6-OHDA模型和其他在基因组编辑，化学和光遗传学，表观遗传学的新技术的背景下，以及对大脑中应激诱导的适应不良机制的进一步研究，都有希望将我们对这种疾病的理解提升到一个新的水平。
Lesch–Nyhan disease is a neurologically, metabolically, and behaviorally devastating condition that has eluded complete characterization and adequate treatment. While it is known that the disease is intimately associated with dysfunction of the hypoxanthine phosphoribosyltransferase 1 (HPRT1) gene that codes for an enzyme of purine metabolism (hypoxanthine-guanine phosphoribosyltransferase) and is associated with neurological, behavioral, as well as metabolic dysfunction, the mechanisms of the neurobehavioral manifestations are as yet unclear. However, discoveries over the past few decades not only have created useful novel animal models (e.g., the HPRT-deficient mouse and the serendipitously discovered perinatal 6-hydroxydopamine (6-OHDA lesion model), but also have expanded into epigenetic, genomic, and proteomic approaches to better understand the mechanisms underlying this disease. The perinatal 6-OHDA model, in addition to modeling self-injury and dopamine depletion in the clinical condition, also underscores the profound importance of development in the differential course of maladaptive progression in the face of a common/single neurotoxic insult at different ages. Recent developments from clinical and basic science efforts attest to the fact that while the disease would seem to have a simple single gene defect at its core, the manifestations of this defect are profound and unexpectedly diverse. Future efforts employing the 6-OHDA model and others in the context of the novel technologies of genome editing, chemo- and opto-genetics, epigenetics, and further studies on the mechanisms of stress-induced maladaptations in brain all hold promise in taking our understanding of this disease to the next level.
影响因子：
25
作者：
Deisseroth K
通讯作者：
Deisseroth K