The pathophysiology of new microcephaly causing mutations in amino acid metabolism provides novel insights in physiological neurotransmitter recycling

引起氨基酸代谢突变的新小头畸形的病理生理学为生理神经递质循环提供了新的见解

• 批准号: 422868836
• 负责人: Professor Dr. Johannes Hirrlinger, Ph.D.
• 金额: --
• 依托单位: Carl-Ludwig-Institut für Physiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/422868836?language=en
• 关键词: pathophysiology; new; microcephaly; causing; mutations

Microcephaly is a devastating condition defined by a small head compared to the age- and sex-matched population, mostly defined as a head circumference more than 3 standard deviations below the age- and sex-matched means. Children with microcephaly often have impaired cognitive development, facial distortions, hyperactivity, seizures and other brain and neurological symptoms. While some patients only show rather mild disabilities, other patients are severely affected and require lifelong intensive care. Both genetic as well as acquired causes have been associated with microcephaly. Numerous genes have been identified, mutations of which are causative for the disease. In a family with two affected children, we identified two new mutations in the asparagine synthetase gene, which has only recently been identified as a microcephaly-causing gene. However, the specific pathophysiology of these mutations affecting primarily the brain but not peripheral organs has not been clarified to date. We hypothesize that – besides synthesizing asparagine – asparagine synthetase has an additional brain-specific function contributing to neurotransmitter recycling in the context of the glutamate-glutamine cycle, a well-studied metabolic interaction of astrocytes and neurons. During glutamate-glutamine cycle activity, ammonium is released from glutamine while regenerating glutamate as a neurotransmitter in neurons. However, despite many years of research on the glutamate-glutamine cycle it has remained enigmatic how ammonium is transferred back to astrocytes, where it is needed for further glutamine synthesis. We hypothesize that asparagine synthetase is crucial for this process and failure of asparagine synthetase function due to mutations will result in ammonium accumulation in neurons, leading finally to neuronal death and microcephaly. Therefore, the first main objective of the proposed project is to identify the mechanism how the mutations in asparagine synthetase found in patients result in the observed severe development impairment and microcephaly. As asparagine synthetase has so far not been considered as a pathway of ammonium clearance in neurons, the second main objective is to resolve the long-standing enigma in neurobiology of how ammonium is transferred back from neurons to astrocytes in the context of the glutamate-glutamine cycle.

小头畸形是一种毁灭性的疾病，定义为与年龄和性别匹配的人群相比头部较小，主要定义为头围比年龄和性别匹配的平均值低3个标准差以上。患有小头畸形的儿童通常有认知发育受损，面部扭曲，多动症，癫痫发作和其他大脑和神经系统症状。虽然有些病人只表现出相当轻微的残疾，但其他病人受到严重影响，需要终身重症监护。遗传和后天原因都与小头畸形有关。许多基因已被确定，其突变是导致疾病的原因。在一个有两个受影响儿童的家庭中，我们发现了天冬酰胺合成酶基因的两个新突变，该基因最近才被确定为导致小头畸形的基因。然而，这些突变主要影响大脑而不是外周器官的具体病理生理学至今尚未阐明。我们假设，除了合成天冬酰胺-天冬酰胺合成酶有一个额外的大脑特定的功能，有助于神经递质的谷氨酸-谷氨酰胺循环的背景下，星形胶质细胞和神经元的代谢相互作用的研究。在谷氨酸-谷氨酰胺循环活动期间，铵从谷氨酰胺释放，同时再生谷氨酸作为神经元中的神经递质。然而，尽管对谷氨酸-谷氨酰胺循环进行了多年的研究，但铵如何转移回星形胶质细胞仍然是个谜，在星形胶质细胞中需要进一步的谷氨酰胺合成。我们假设，天冬酰胺合成酶是至关重要的，这一过程和故障的天冬酰胺合成酶的功能，由于突变将导致铵积累在神经元中，最终导致神经元死亡和小头畸形。因此，该项目的第一个主要目标是确定患者中发现的天冬酰胺合成酶突变如何导致观察到的严重发育障碍和小头畸形的机制。由于天冬酰胺合成酶迄今尚未被认为是神经元中铵清除的途径，第二个主要目标是解决神经生物学中长期存在的谜团，即在谷氨酸-谷氨酰胺循环的背景下，铵如何从神经元转移回星形胶质细胞。