Elucidating the consequences of aberrant mGluR1 signalling in cerebellar ataxia

Ataxia comes from the Greek word 'a taxis' meaning 'lack of order'. Patients suffering from ataxia have problems with their movement, balance and speech, and sometimes develop cognitive disabilities. We study a subgroup of cerebellar ataxias, termed 'spinocerebellar ataxias' (SCAs). These are brain disorders that are caused by the malfunctioning and death of specific nerve cells in the cerebellum, a part of the nervous system that controls movement and coordination. There is currently no cure for SCAs. SCAs are inherited diseases, which means that they are caused by faulty genes, which are passed down through families. Many different genes can cause SCAs, and this presents a great challenge to our understanding of these disorders and, importantly, to efforts in developing potential treatments.
Our work focuses on one specific pathway (mGluR1-TRPC3) that regulates the calcium balance within nerve cells and that is commonly disturbed in SCAs. Thus, this pathway provides an exciting novel therapeutic target for SCAs, which we will explore further with the proposed research. Our findings will provide important insights into molecular and cellular processes that go awry in the cerebellum when the mGluR1-TRPC3 pathways is abnormally active. We will study the novel mutations in mGluR1 that we have identified in SCA patients in cell lines, cerebellar nerve cells and a new mouse model. This will shed light on the mechanisms of how these mutations cause disease. We will then use the assays that we have established to identify readily-available and safe drugs that could be used for treatment of SCAs.

The spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders characterized by the progressive dysfunction of the cerebellum resulting in a loss of motor coordination. No effective treatments exist for the SCAs, and there is thus a pressing need for better models in which to study the underlying disease-causing mechanisms and to identify potential therapies.
Aberrant mGluR1-TRPC3 signalling and downstream dysregulation of calcium homeostasis has been hypothesized as a key pathological event in several distinct genetic forms of cerebellar ataxia, but the underlying mechanisms remain unclear. Recently, we were the first to identify dominant gain-of-function mutations in the GRM1 gene - encoding mGlur1 - in patients with SCA44. Here, we will take a multi-facetted approach to elucidate the molecular and cellular mechanisms by which mutant mGluR1 causes cerebellar ataxia and to identify small molecule compounds that could be used as potential therapeutics. We will functionally characterize the novel mutations that we have identified in cellular assays including in primary Purkinje cells. We have already generated the first mouse model for SCA44 that carries one of the patients' gain-of-function mutation in Grm1. We propose to carry out a detailed investigation of the disease phenotypes in this mouse related to both motor and cognitive dysfunction. We will subsequently exploit the identified in vitro and in vivo SCA44 phenotypes to identify compounds that modulate the disease. We have already identified lead compounds that might have therapeutic benefits including the FDA-approved drug Nitazoxanide and a novel potent TRPC3 antagonist that we propose to further explore. Together, our research will provide a platform for drug discovery in SCA44 and related ataxias and identify promising molecules that could be of therapeutic benefit for these disorders.

Although individually rare, the group of hereditary cerebellar ataxias comprises more than 100 different genetic forms ,and it is estimated that there are at least 10,000 adults and 500 children in the UK alone with a progressive ataxia (Source: Ataxia UK). Thus, this disease places a significant social and economic burden to society, and research into ataxia is an area of both unmet medical and economic need.
Our research will contribute to a better understanding of the disease mechanisms in SCA44 and related disorders. Notably, as the affected mGluR1 signalling is linked to several genetically distinct ataxias, our findings promise to provide novel insights into the pathogenesis not only of SCA44 but also other genetic forms of SCAs. This is in line with the strategic plan of the MRC, which seeks 'to strengthen our knowledge of cellular and molecular neurological mechanisms and the function of the brain and how this relates to mental health and disease'. Ultimately, we hope that our findings will lead to improved therapeutic options for patients with cerebellar ataxia and other brain disorders, where mGlur1 signalling is affected. Together, our work will impact on researchers, patients, charities and the pharmaceutical industry and will have wider benefits for our society's health and wellbeing.
The immediate impact of our study will be on the wider academic community by contributing to our understanding of the disease mechanisms in cerebellar ataxia. Moreover, our work will provide attractive novel models to study SCA44 and cerebellar disorders in general. This study will also have an immediate impact on the post-doc and the research assistant, who will work on this project, as well as undergraduate and graduate students in the lab. These scientists will learn new techniques and gain experience in critical thinking and experimentation and also presentation, writing and networking. Employed staff will also be encouraged to attend courses that will further develop their transferable skills and advance their career development such as management, leadership, teaching and effective communication.
Our research will also have societal and economic impacts. We are committed to public engagement of science and will widely communicate our research activities through participation in science festivals and public talks, thus enabling members of the public to act as informed citizens. We also work with school pupils, particularly through the national In2Science programme for Year 12 science students from low-income backgrounds, to inspire the next generation of researchers and provide them with the knowledge and confidence to progress to University.
SCA44 is a recently-described disease. Our work will raise awareness and provide clinical geneticists and clinicians with more information about the spectrum of GRM1 mutations, genotype-phenotype relationships and pathogenesis, thereby enabling them to engage better with patients and to offer targeted genetic screening. Similarly, our work will inform ataxia charities better about the disease and also about our developed technologies, leading to improved patient awareness and engagement.
In the longer term, it is likely that potential targets and therapeutics identified in our study will lead to the discovery or repurposing of a drug for cerebellar ataxia. This work should thus be of commercial interest to the pharmaceutical industry.
Ultimately, we hope that our study will be beneficial for patients that suffer from cerebellar ataxia and thus of benefit for the nation's well-being and quality of life.