Neuronal Arginine Metabolism in Health and Disease

Mental illnesses caused by major depression and anxiety disorders (MDD/AD) are among the greatest challenges in modern societies, with rapidly increasing incidence, high risk of suicide and developing chronic illnesses, economic burden on healthcare systems. The COVID19 pandemic with repeated periods of social isolation and personal health and economic uncertainties has amplified this phenomenon, overwhelming health services. The neurons are brain cells encoding feelings and emotions. Neurons communicate with cerebral chemicals called neurotransmitters. The imbalance between excitatory and inhibitory neurotransmitters is considered the main cause of MDD/AD favoured by chronic stress. Drugs targeting neurotransmitters show efficacy for patients with MDD/AD but are slow-acting with delays in months before reaching efficacy, cause uncomfortable side-effects preventing long-term drug administration and are inefficient in a large minority of patients. Novel therapies are urgently required to fill these unmet needs.

Arginine is a biochemical called amino acid, the elementary constitutive part of proteins. Arginine is a precursor for various other small molecules, which influence cellular energy, regulation of genes, cross-talk between neurons and astrocytes. However, little is known about the exact role of the arginine pathways in MDD/AD.

The aim of my project is to understand how the arginine pathways can impact the functioning of neuron-astrocyte interactions, called coupling, and its consequences for MDD/AD. To achieve this, I will use a rare genetic disease, which causes low arginine levels in brain cells as a model. Argininosuccinate lyase (ASL) is the only catalyst or enzyme in humans, 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, epilepsy, anxiety and psychiatric symptoms in patients.

I have observed that ASL-deficient models present anxiety behaviour. I will use these models to study the regulation of arginine pathways in the brain, monitor anxiety and depression through behavioural testing, assess electrical encoding and retention of information in neurons. I will use human "stem" cells which can be reprogrammed as neurons and astrocytes to form 3-dimensional mini-brains in a dish to assess if ASL deficient mini-brains can help understanding electrical features of impaired neuron-astrocyte coupling. I will use gene therapy approaches to treat ASL-deficient models.

On completion, this work will provide a clear understanding of the impact of the arginine pathways on neuron-astrocyte coupling and molecular cause of anxiety and depression in ASL-deficient models. This will enable to identify and validate targets to generate novel therapies to improve or even reverse the pathological process observed in this rare disease. This work might provide opportunities to generate novel drugs, which could have a significant long-term medical impact for MDD/AD. Thus, this could benefit a large number of patients and the healthcare system.

Major depression and anxiety disorders (MDAD) are leading public health burden, exacerbated by the COVID19 pandemic, with limited efficient therapies and reliable preclinical models. Arginine metabolites, e.g. nitric oxide (NO), polyamines, play key-role in neurotransmission and brain energy homeostasis. Dysregulated arginine metabolism observed in neurodevelopment, neurodegeneration and mental health diseases highlights the importance of this pathway for brain physiology. How arginine metabolism can affect mental health is unclear. In this proposal, I will use the inherited deficiency of argininosuccinate lyase (ASL), the only enzyme synthesising arginine, as a model to interrogate the effect of arginine deprivation on chronic stress and synaptic plasticity, and to identify novel therapeutic targets.
I hypothesize that the psychiatric symptoms observed in ASLD are caused by impaired neuron-astrocyte coupling. Developing innovative and efficient therapies for MDAD is hampered by limited reliable preclinical models. I will investigate ASLD as a surrogate model to study impaired arginine pathway in MDAD. I will study translatable hASLenhancing gene therapies to treat psychiatric symptoms in ASLD, to substantially understand how impaired arginine metabolism affects MDAD.
This project will develop world-leading research to tackle the major public healthcare burden of MDAD with increasing incidence and unmet needs. Additionally, this work might have some implications in autism spectrum disorders and schizophrenia. The potential discoveries of this project could lead to applications in identifying new therapeutic targets not only for inherited ASLD but for common psychiatric and neurodevelopmental disorders too. Therefore, there is huge potential for the outputs of this research to inform future drug discovery in a various range of rare and common diseases.