Exploring astrocytic orphan G-protein coupled receptors as potential targets for neuroprotective therapies

Contrary to the commonly held view, the most abundant cell type in the brain are not the excitable nerve cells usually called neurones but another cell type which is smaller and often has a star-shape morphology, hence is called "astrocyte". While computation is performed by neurones, they critically depend on astrocytes which control the environment in which neurones live and operate. Astrocytes regulate the supply of nutrients and supporting (trophic) factors to neurones, levels of ions around neurones and, in addition, signal to neurones in a variety of ways. Neurones cannot live without this input from astrocytes. Many of the most devastating chronic disorders of the brain have a component of neurodegeneration where some populations of neurones become dysfunctional over time or die. Examples of such diseases are Parkinson's disease, Alzheimer's disease and other types of dementia, each being a huge medical, social and economic burden. Traditionally the approaches to treatment of such diseases assumed that the best way is via therapies directed at neurones. The clinical progress, however, has been slower than desired and anticipated. An alternative view is to search for pathways to modulate astrocytes with the aim to improve their trophic function on neurones and thus indirectly improve neuronal survival and function.
Approximately 15 years ago scientists found in the brain a receptor for an unknown signalling molecule. It was called GPR37 (G-protein coupled receptor 37) and immediately attracted attention because of it is high concentration in the brain. However, without knowing which molecular messenger activates GPR37, understanding of its function has been painfully slow although, indirectly, it was possible to link it to neurodegeneration. In parallel, another line of research investigated prosaposin, a protein present in the brain. It was established without any doubt that prosaposin is very important for the survival of brain neurones. Various hypotheses have been put forward about its mechanism of action but none of them became commonly accepted. A recent discovery brought these two lines of scientific enquiry together. It was found that prosaposin activates GPR37 and thus it is most likely that the prosaposin-GPR37 pathway is of major importance for the health of the brain.
While analysing gene expression in astrocytes we have by serendipity noticed that GPR37 is present in astrocytes at extraordinary high levels. Careful analysis of previously published literature demonstrates that earlier studies also had evidence consistent with the idea that the prosaposin-GPR37 pathway is a predominantly astrocytic signalling mechanism. Our key hypothesis is that prosaposin (or shorter proteins derived from it) stimulate GPR37 on astrocytes and change their function in some way to improve their communication with neurones and engage their trophic functions. Based on the previous literature we hypothesise that this mechanism could be particularly important for survival of a specific subset of neurones which release chemicals known as catecholamines, including neurones which are known to be damaged in Parkinson's and Alzheimer's diseases. Before we can engage in more complex experiments and drug design we want to test this idea using well established in vitro methods in experiments on cultured brain explants. Our approach is through a combination of molecular, electrochemical and imaging techniques some of which we have developed ourselves.
If our hypothesis is correct, this may lead to a new family of drugs with completely novel properties, possibly offer a new strategy for treatment of various neurodegenerative disorders, and hopefully improve prognosis and the quality of life of numerous patients. Given the overwhelming economic burden of these diseases, even a small improvement in their therapy will save billions of pounds.

The current project aims to explore a new avenue for treatment of neurodegenerative disorders, such as Parkinson's or Alzheimer's disease, and possibly others where destruction of catecholaminergic neurons is prominent. In contrast to most previous research which targeted neurones directly, we propose to explore the potential of a neuroprotective pathway mediated by astrocytes. Astrocytes express two closely related orphan G-protein-coupled receptors GPR37 and GPF37L1 at extraordinarily high levels. It has very recently been found that the natural ligand for these receptors is prosaposin, a peptide with essential neuroprotective properties. Previous research has implicated GPR37 and GPR37L1 in control of viability of catecholaminergic neurones. Although GPR37 and GPR37L1 and highly expressed in astrocytes, we know essentially nothing of their actions in these cells or the downstream consequences for neurones. We propose an exploratory project which will inform us about prosaposin-induced GPR37/GPR37L1 mediated effects on astrocytes and test the idea that this pathway improves survival and transmitter release by dopaminergic and noradrenergic neurones in vitro. The project involves profiling of GPR37 and GPR37L1 in astrocytes from different parts of the rodent brain; evaluation of the effects of prosaposin on cultured astrocytes and of the roles of GPR37 and GPR37L1 in its actions; development of knock-down vectors for these receptors; and tests in vitro for the role of this pathway in neuroprotection using a synthetic analogue of prosaposin, prosaptide. These studies will provide a theoretical base for drug development and further exploitation of the prosaposin-GPR37/GPR37L1 pathway. Given that G-protein-coupled receptors constitute approximately 40% of current drug targets, we may well be facing the opportunity to develop a new class of drugs which would operate via GPR37/GPR37L1-mediated neuroprotective functions of astrocytes.

The purpose of this project is to explore a new therapeutic strategy for treatment of neurodegeneration via modulation of signalling pathways in astrocytes. There is every reason to believe that the pathway we propose to study plays a major role in well-being of a healthy brain.
We aim to provide the theoretical base for development of glia-targeted drugs operating via specific GPCRs abundant on astrocytes. Since this is key to further rational therapeutic approaches, this work has the potential to lead to improvement of the nation's health and increase the quality of life of numerous patients with diverse neuro-degenerative disorders.

The present project is exploratory and paves the way to development of targeted therapies which could potentially benefit patients with Parkinson's disease, dementia and other neuro-degenerative conditions, including apparently divergent disorders such as hypertension and chronic pain. All these diseases represent major medical, social and economic problems with unmet demand for better treatments. Even a small positive step in these directions would have a huge positive impact on health and wealth of the nation. Firmly establishing GPR37/GRP37L1 as drug targets is bound to attract the interest of drug industry and stimulate industrial research in this direction thus helping to retain skilled national workforce. Hence beneficiaries could be within both public and private sector. We believe that within the next decade we may have clinically used drugs working via the pathway we aim to explore.

Other beneficiaries include those who will be trained in various techniques (imaging, optogenetics, molecular biology, electrochemistry) in the course of this project, thus increasing their professional skills and employment prospects. This includes a new postdoctoral researcher, PhD students and undergraduate project students (Physiology, Neuroscience, Pharmacology, MSc in Biomedical Sciences Research).

If our hypothesis is correct, this may lead to a new family of drugs with completely novel properties, possibly offer a new strategy for treatment of various neurodegenerative disorders, and hopefully improve prognosis and the quality of life of numerous patients. Given the overwhelming economic burden of these diseases, even a small improvement in their therapy will save billions of pounds.