MICA: Neuronal Arginine Metabolism in Health and Disease

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.

Arginine downstream metabolites play key-roles in neurotransmission, cellular bioenergetics, gene regulation. These metabolites (i.e. nitric oxide (NO), creatine, polyamines) are involved in various pathophysiological processes e.g. immunology, inflammation, tumorigenesis, but also in schizophrenia and neurodegenerative diseases, highlighting the importance of this pathway in brain physiology and suggesting the relevance of arginine-targeted therapy for some neurodevelopmental or neurodegenerative diseases.

Argininosuccinate lyase (ASL) is the only mammalian enzyme enabling endogenous arginine synthesis. The ubiquitously expressed ASL enzyme belongs to the urea cycle, detoxifying nitrogen waste, and the citrulline-NO cycle, essential for NO synthesis from NO synthase.

Inherited ASL deficiency (ASLD) causes hyperammonaemia, arginine deprivation and NO deficiency, features of argininosuccinic aciduria. Compared to other urea cycle defects, ASLD shows rarer hyperammonaemic decompensations and a systemic phenotype with developmental delay unrelated to hyperammonaemia. In previous work, I showed that, similarly to humans, ASLD mice present memory deficit, independent of hyperammonaemia and neuroinflammation, and neuronal oxidative/nitrosative stress.

This project aims to unravel the role of arginine in neuronal biology using ASLD as a model to interrogate the effect of arginine deprivation on neuronal biology and to identify therapeutic targets.

I will study the impact of arginine deprivation on (i) neuronal bioenergetics and antioxidant pathways and mitochondrial function, (ii) neuronal plasticity and neurotransmission, and (iii) assess if ASLD can be a reliable disease model to better understand features of neurodegenerative diseases. On completion, this work will provide a clear understanding of the impact of arginine metabolism on key neuronal functions and its putative role in neurodegeneration.

The primary research aim is to understand the role of arginine metabolism (i.e. arginine and its downstream metabolites as nitric oxide, creatine, polyamines) in neuronal biology and subsequent effects on learning and memory. The key objectives are to 1) identify the impact of intracellular arginine deprivation on neuronal bioenergetics, antioxidant pathways and mitochondrial function, 2) assess the effect of arginine deprivation on neurotransmission and neuroplasticity, 3) assess if ASLD can be a reliable disease model to understand the features of altered arginine metabolism observed in some neurodegenerative diseases like Alzheimer's disease. On completion, this work will provide a clear understanding of the impact of arginine metabolism on key neuronal functions and his role in neurodegeneration.

1. The outcomes of my research have potential socio-economic and academic benefits worldwide. They also have possible broader applications as arginine metabolism is critical in various physiological and pathophysiological processes, such as inflammation, immunology, tumorigenicity, neurodevelopment, neurodegeneration. By advancing our understanding of the fundamental mechanisms by which arginine metabolism influence neuronal biology and functions, the output of this fellowship will directly benefit RESEARCHERS studying cell biology, neuronal plasticity, neurodegeneration, arginine metabolism. Furthermore, as impaired arginine metabolism is associated with deficient memory in an inherited form of arginine deficiency, argininosuccinate lyase, and in some neurodegenerative diseases, this research will inform researchers and clinicians working on a broad range of inherited and acquired disorders.

2. The GENERAL PUBLIC will benefit from this research, as e.g. of neurodegenerative disease, i.e. Alzheimer's disease, a common public health problem and NHS priority. The discovery of novel potentially curative approach to treatment for these diseases will be of interest for patients, families and communities facing these devastating diseases. I will engage the UCL Public Engagement Unit as well as our Institute website to provide educational information about arginine metabolism and its impact in neuronal biology, and application in inherited ASL deficiency and neurodegeneration.

3. By identifying key mechanisms and cellular pathways, there is a huge potential that this research could inform therapeutic targets and future drug discovery. The outputs of this fellowship are therefore likely to benefit the PHARMACEUTICAL INDUSTRY if new knowledge about therapeutic targets and potential for translation arise from this work. I will pursue this potential translational benefit through support from UCL Translational Research Office and ensure potential commercial exploitation is maximised with the expert advice of UCL Business. In the long term there may be impact on the well-being and quality of life of patients as well as economic benefits by saving health care costs also initiating activities in the UK-based pharmaceutical industry.