A faulty gene that starves brain cells of the amino acid arginine causes severe memory problems—and the same metabolic disruption may drive memory loss in Alzheimer’s disease. Arginine is a building block of proteins and a precursor for molecules that control energy use, gene regulation, and communication between neurons. The brain consumes 20% of the body’s oxygen and 25% of its glucose, and memory formation is an energy-intensive process. Yet the precise role of arginine in that process is unknown. This project uses a rare genetic disorder—argininosuccinate lyase (ASL) deficiency, which lowers arginine levels and causes memory deficits—as a model to study how arginine affects neuronal energy pathways, electrical signalling, and behaviour. The researcher will also reprogram human stem cells into neurons to test whether ASL-deficient cells replicate the features seen in genetic forms of Alzheimer’s. If successful, this work will identify specific molecular targets for new therapies. Those could slow or reverse neuronal loss not only in age-related diseases like Alzheimer’s—which affects 7% of people over 65 and is predicted to cost the NHS £25 billion annually—but also in conditions involving inflammation or developmental brain disorders. This is fundamental science: it asks how a single amino acid shapes the basic machinery of memory. Past discoveries in amino acid metabolism have led to treatments for metabolic diseases; a clearer picture here could open similarly unexpected routes to therapy.
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Arginine is a small biochemical compound called amino acid, the elementary constitutive part of proteins. Various observations have suggested that arginine is critical in the formation and retention of memory as impaired arginine metabolism can lead to memory deficit as reported in either genetic diseases affecting arginine metabolism or age-related cerebral diseases with reduction of the brain volume, and loss of the brain cells encoding memory, the neurons. Age-related diseases like Alzheimer's disease are an ever-growing public health problem as it affects 7% of people aged 65 years or over, and are predicted to affect 2 million people by 2050 in the UK. This leads to highly dependent patients with complete loss of autonomy, which is a dramatic burden for families, communities and society. It is estimated to cost £25 billions per year over the next 40 years to the National Health Service (Source Alzheimer's Society; https://www.alzheimers.org.uk accessed 14/03/2019). The brain accounts for only 2% of total body weight but consumes about 20% of the oxygen and 25% of the glucose taken into the human body, the highest energy requirement compared to other organs. Learning and memory relies on highly-energy consuming encoding processes in neurons. Arginine is a precursor for various other small molecules, which influence cellular energy, regulation of genes, cross-talk between neurons. However little is known about the exact role of arginine in memory encoding and retention. The aim of my project is to understand how arginine can impact the functioning of specialised memory cells, the neurons. To achieve this, I will use a rare genetic disease, which causes low arginine levels in cells as a model. Argininosuccinate lyase (ASL) is the only catalyst or enzyme in humans and large animals, which enables the final step of arginine production. ASL deficiency causes a genetic disease with low arginine in all organs, associated with a memory deficit in encoding, retention and information processing in patients. I will use ASL deficient models to study the regulation of energy pathways in the brain, monitor learning and memory through behavioural testing, assess electrical encoding and retention of informations in neurons. I will use human "stem" cells which can be reprogrammed into other specialised cells like neurons to assess if ASL deficient neurons can reproduce and help understanding energetic and electrical features of neurons with genetic forms of Alzheimer's disease. On completion, this work will provide a clear understanding of the impact of arginine metabolism on key functions of neurons in genetic and age-related diseases. This will enable to identify targets to generate novel therapies to improve or even reverse the pathological process observed in these diseases. This work might provide opportunities to generate novel drugs, which could have a very significant long-term medical impact for various purposes including neuronal loss associated with age, but as well caused by inflammation and errors of brain development. Thus, this could benefit a large number of patients and provide significant savings for the healthcare system.
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