Investigating the role of overactive mGluR1 signalling in cerebellar development and disease

Ataxia comes from the Greek word 'a taxis' meaning 'lack of order'. Patients suffering from ataxia have problems with movement, balance and speech, and sometimes develop cognitive disabilities. These clinical symptoms significantly impair patients' quality of life, and many ataxias lead to premature death. Many ataxias have genetic origins. 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). There are few disease-modifying drugs for ataxias available and thus, these conditions represent diseases with a significant unmet medical need.
Our work focuses on the spinocerebellar ataxias (SCAs), a group of dominantly inherited disorders that affect the cerebellum, the part of the brain responsible for movement and balance. Although it is believed that SCAs are caused by the degeneration of the cerebellum over time, recent research suggests that the problem may originate from disrupted cerebellar development early in life. This project aims to better understand the mechanisms that cause abnormal development of the nerve cells in the cerebellum and contribute to the disease. We will focus specifically on the role of aberrant functioning of the metabotropic glutamate receptor mGluR1. mGluR1 is a membrane-bound receptor highly expressed in the cerebellum that plays a crucial role during normal development of this brain structure and has been linked to various SCAs. We will analyse the earliest structural, functional and molecular changes that arise from abnormal mGluR1 signalling. By understanding these early developmental disturbances, we hope to open new avenues for treatment that could delay or prevent the progression of SCA and lead to lead to improved therapeutic options for patients.