The Glycine Cleavage System in Brain Development, Function and Disease

我们的目标是了解甘氨酸脱羧酶(GLDC)蛋白功能受损是如何导致大脑发育和功能障碍的。GLDC的作用是分解一种名为甘氨酸的小分子，允许部分分子进入被称为叶酸代谢的化学反应网络，这是几乎所有细胞都需要的，以实现许多不同的功能。GLDC活性的丧失，例如由遗传基因突变引起，会导致过量甘氨酸的积累和叶酸代谢的抑制。我们的目标是了解这些变化如何导致出生前和出生后都会出现的危及生命的脑部疾病。这些疾病包括常见的出生缺陷，如神经管缺陷(NTDS)和先天性脑积水，以及严重的儿童疾病非酮症高血糖(NKH)。叶酸代谢异常会导致NTDS、脑积水和NKH。了解因果联系也具有更广泛的相关性，因为叶酸代谢与一系列其他疾病(如出生缺陷、癌症和神经疾病)有关，并可能因遗传基因变化和其他因素(如饮食)而改变。NTDS发生在大约每1000个妊娠中有1-2个，原因是神经管形成不完整，后来发育到大脑和脊髓。胎儿的大脑和/或脊髓会受到不可逆转的损害，导致出生前后死亡或幸存儿童长期残疾。由于许多可能的因素，每个人NTDS的确切原因通常是未知的。研究GLDC缺陷是如何导致NTDS的，为更好地了解叶酸代谢和NTDS之间的联系提供了机会。先天性脑积水每1000名婴儿中就有0.5-1例，并可由于脑内脑脊液压力增加而导致脑损伤。由GLDC突变引起的脑积水是由于胎儿大脑结构的错误构建导致液体流动受阻所致。导致目前这项研究的工作表明，这是叶酸代谢受损的结果。下一步是确切地了解大脑发育过程何时以及在哪些细胞中出错，叶酸代谢的哪些输出受到干扰，以及这些变化是否导致脑积水。除了导致NTDS和脑积水外，GLDC突变还是NKH的主要原因，NKH是一种遗传性疾病，每50,000名婴儿中就有1人受到影响，并导致癫痫、严重的发育迟缓和过早死亡。甘氨酸过多和叶酸代谢受损对NKH不同方面的相对贡献尚不清楚，我们将解决这个问题。如果母亲在怀孕前或怀孕早期补充叶酸(与叶酸有关)，患NTDS的风险可以大大降低。然而，相当数量的NTDS对叶酸具有抗药性，有必要确定其他治疗方法。一个关键的目标是确定新的预防NTDS和脑积水的方法，这些方法可以单独使用或与叶酸联合使用。在已确定遗传风险因素的家庭中，这也意味着可以提供针对家庭的治疗方法。目前治疗NKH的方法并不有效，也没有治愈方法。为了实施新的治疗方法，了解NKH的某些特征是否源于出生前已经表现出的异常以及这些异常是否可以纠正是重要的。我们将使用缺乏GLDC功能的小鼠和人类细胞模型来解决NTDS、脑积水和NKH机制的关键悬而未决的问题。这些模型提供了一个机会来确定GLDC缺陷对叶酸代谢和相关生化反应的准确影响，这些影响如何导致对大脑发育至关重要的前体细胞的变化，以及特定的细胞组在出生后是否在大脑中异常。

We aim to understand how impaired function of the glycine decarboxylase (GLDC) protein leads to disorders of brain development and function. GLDC acts to break down a small molecule called glycine, allowing part of the molecule to enter a network of chemical reactions known as folate metabolism, which is needed in almost all cells for many different functions. Loss of GLDC activity, resulting for example from an inherited genetic mutation, leads to accumulation of excess glycine and to suppression of folate metabolism. Our goal is to understand how these changes lead to life-threatening brain diseases that arise both before and after birth. These disorders include common birth defects such as neural tube defects (NTDs) and congenital hydrocephalus, as well as the severe childhood disease Non-Ketotic Hyperglycinemia (NKH). Abnormal folate metabolism contributes to NTDs, hydrocephalus and NKH. Understanding causal links is also of broader relevance as folate metabolism is implicated in a range of other disorders (e.g. birth defects, cancers, and neurological disease), and may be altered by inherited genetic changes and other factors such as diet.NTDs occur in approximately 1-2 per 1,000 pregnancies, due to incomplete formation of the neural tube, which later develops into the brain and spinal cord. The brain and/or spinal cord of the fetus become irreversibly damaged, resulting in death around birth or long-term disability in surviving children. Because of the many possible contributory factors, the exact cause of NTDs in each individual is usually unknown. Working out how GLDC defects cause NTDs provides an opportunity to gain a better understanding of the link between folate metabolism and NTDs.Congenital hydrocephalus affects 0.5-1 per 1,000 babies and can lead to brain injury owing to increased pressure of cerebrospinal fluid within the brain. Hydrocephalus caused by GLDC mutation results from a blockage of fluid flow due to incorrect building of the fetal brain structure. Work leading to the current study shows that this is a result of impaired folate metabolism. The next step is to understand exactly when and in which cells the process of brain development goes wrong, which of the outputs of folate metabolism are disrupted, and whether these changes are responsible for hydrocephalus. In addition to contributing to NTDs and hydrocephalus, GLDC mutation is the major cause of NKH, an inherited disease that affects around 1 per 50,000 babies and causes epilepsy, profound development delay and early death. The relative contribution of excess glycine and impaired folate metabolism to different aspects of NKH is not well understood and we will address this question. The risk of NTDs can be substantially reduced if the mother takes supplemental folic acid (related to folate) supplements before or during early pregnancy. However, a substantial number of NTDs are resistant to folic acid and there is a need to identify additional therapies. A key aim is to identify new preventive therapies for NTDs and hydrocephalus which may be used individually or in combination with folic acid. In families where genetic risk factors have been identified this also means that family-specific therapies may be offered. Current treatments for NKH are not effective and there is no cure. In order to implement new therapies it is important to understand whether some features of NKH result from abnormalities that already manifest before birth and whether these can be corrected.We will address key outstanding questions about the mechanisms underlying NTDs, hydrocephalus and NKH using mouse and human cell models lacking function of GLDC. These models provide an opportunity to determine the precise effects of GLDC defects on folate metabolism and linked biochemical reactions, how these lead to changes in precursor cells that are essential for brain development and whether particular groups of cells are abnormal in the brain after birth.