Novel therapy for monoamine neurotransmitter deficiency in PKU

项目摘要 本计画的总体目标是探讨认知缺陷和神经精神症状的病因 与苯丙酮尿症（PKU）相关，苯丙酮尿症是最常见的先天性代谢缺陷之一， 新生儿筛查许多青少年和成年人与PKU斗争坚持推荐的饮食 疗法慢性高苯丙氨酸血症经常与焦虑、抑郁和神经功能受损有关。 执行功能，如注意力集中和短期记忆困难。缺陷 脑内的单胺类神经递质多巴胺和5-羟色胺可能与 PKU神经行为障碍的原因。在我们最近对Pahenu 2小鼠的研究中， PKU表现出记忆缺陷和焦虑，我们发现大脑多巴胺含量相对较低， 但在未经治疗的成年小鼠中血清素严重缺乏。最有可能导致 Pahenu 2小鼠脑5-羟色胺缺乏是苯丙氨酸介导的TPH活性竞争性抑制 导致血清素合成受损给予以下任一种药物后纠正高苯丙氨酸血症 苯丙氨酸限制饮食或肝脏定向基因治疗导致大脑血清素含量增加， 改善焦虑行为，但记忆力没有变化。这些结果与成人中观察到的结果相似 患有PKU的人，他们在生命早期接受了晚期治疗，并在生命早期遭受了不可逆的大脑损伤。 开始饮食治疗。我们的假设是，高苯丙氨酸血症小鼠的焦虑是由 中枢神经系统5-羟色胺缺乏症，但记忆缺陷是其他更永久性异常的结果 从婴儿期开始的长期高苯丙氨酸血症导致的大脑发育。在 我们项目的第一个目标，我们将继续探索大脑5-羟色胺和焦虑之间的关系， pahenu 2/enu 2小鼠，并评估针对这种并发症的新的治疗方法。第二个目标 在我们的项目中，我们将开发和描述一种新的PKU模型，更类似于 通过新生儿筛查发现的当代PKU成人， 通过用重组苯丙氨酸治疗Pahenu 2/enu 2新生儿， 氨裂解酶（PAL，Pegvaliase）用于控制整个婴儿期和成年期的血液苯丙氨酸。我们 将比较PAL治疗和未治疗之间的行为结果、神经病理学和神经化学 pahenu 2/enu 2小鼠，并进一步研究高苯丙氨酸血症复发的后果， 停止PAL治疗。我们认为PAL处理的Pahenu 2/enu 2小鼠将更有效地模拟 当代PKU治疗的现状，并将提供新的见解PKU的性质- 相关的神经认知缺陷。

PROJECT SUMMARY The overall goal of this project is to investigate the etiology of cognitive deficits and neuropsychiatric symptoms associated with phenylketonuria (PKU), one of the most common inborn errors of metabolism detected through neonatal screening. Many adolescents and adults with PKU struggle with adherence to recommended dietary therapy. Chronic hyperphenylalaninemia is frequently associated with anxiety, depression, and impaired executive function such as difficulties with concentration and short-term memory. Deficiencies of the monoamine neurotransmitters, dopamine and serotonin, in brain have been implicated as probable proximal causes of neurobehavioral difficulties in PKU. In our recent work with the Pahenu2 mouse, a model of human PKU that exhibits both a memory deficit and anxiety, we have found that brain dopamine content is relatively undisturbed but that serotonin is severely deficient in untreated adult mice. The most likely mechanism causing brain serotonin deficiency in Pahenu2 mice is phenylalanine-mediated competitive inhibition of TPH activity leading to impaired serotonin synthesis. Correction of hyperphenylalaninemia following administration of either a phenylalanine restricted diet or liver-directed gene therapy leads to increased brain serotonin content and improved anxiety behaviors but no change in memory. These outcomes are similar to those seen in adult humans with PKU who were late treated and suffered irreversible damage to the brain early in life prior to the initiation of dietary therapy. Our hypotheses are that anxiety in hyperphenylalaninemic mice is caused by CNS serotonin deficiency but that the memory deficit is a result of other more permanent abnormalities of brain development resulting from long standing hyperphenylalaninemia beginning in infancy. In the first aim of our project, we will continue to explore the relationship between brain serotonin and anxiety in Pahenu2/enu2 mice and to evaluate novel therapeutic approaches directed at this complication. In the second aim of our project, we will develop and characterize a novel model of PKU, more analogous to the status of contemporary adults with PKU who were detected by newborn screening, received dietary treatment early in life, but subsequently lost dietary control, by treating Pahenu2/enu2 neonates with recombinant phenylalanine ammonia lyase (PAL, Pegvaliase) to control blood phenylalanine throughout infancy and into adulthood. We will compare behavioral outcomes, neuropathology and neurochemistry between PAL-treated and untreated Pahenu2/enu2 mice and furthermore will study the consequences of remerging hyperphenylalaninemia upon discontinuation of PAL treatment. We propose that PAL-treated Pahenu2/enu2 mice will more effectively model the current status of contemporary PKU treatment and will provide novel insights into the nature of PKU- associated neurocognitive deficits.