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

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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.