Elucidating the consequences of aberrant mGluR1 signalling in cerebellar ataxia

共济失调源于希腊语中的“a axis”，意思是“缺乏秩序”。共济失调患者在运动、平衡和语言方面存在问题，有时还会出现认知障碍。我们研究了小脑性共济失调的一个亚组，称为脊髓小脑性共济失调(SCAs)。这些大脑疾病是由小脑中特定神经细胞的故障和死亡引起的，小脑是控制运动和协调的神经系统的一部分。目前还没有治愈SCA的方法。SCA是遗传性疾病，这意味着它们是由缺陷基因引起的，这些缺陷基因会在家族中遗传。许多不同的基因可以引起SCA，这对我们对这些疾病的理解提出了巨大的挑战，更重要的是，对开发潜在治疗方法的努力也是如此。我们的工作集中在一条特定的通路(mGluR1-TRPC3)上，该通路调节神经细胞内的钙平衡，在SCA中通常受到干扰。因此，该途径为SCA提供了一个令人兴奋的新的治疗靶点，我们将在拟议的研究中进一步探索这一点。我们的发现将为当mGluR1-TRPC3通路异常活跃时小脑中出现错误的分子和细胞过程提供重要的见解。我们将研究我们在SCA患者的细胞系、小脑神经细胞和一个新的小鼠模型中发现的mGluR1的新突变。这将阐明这些突变如何导致疾病的机制。然后，我们将使用我们建立的分析方法来确定可用于治疗SCA的现成和安全的药物。

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.