Elucidating the consequences of aberrant mGluR1 signalling in cerebellar ataxia

共济失调来自希腊语“a taxis”，意思是“缺乏秩序”。患有共济失调的患者在运动、平衡和言语方面存在问题，有时还会出现认知障碍。我们研究了小脑共济失调的一个亚组，称为“脊髓小脑共济失调”（SCA）。这些是由小脑中特定神经细胞的功能障碍和死亡引起的大脑疾病，小脑是神经系统的一部分，控制运动和协调。目前还没有治愈SCA的方法。SCA是一种遗传性疾病，这意味着它们是由有缺陷的基因引起的，这些基因通过家庭传递。许多不同的基因可以导致SCA，这对我们理解这些疾病提出了巨大的挑战，重要的是，开发潜在治疗方法的努力。我们的工作集中在一个特定的途径（mGluR 1-TRPC 3），调节神经细胞内的钙平衡，这是在SCA中常见的干扰。因此，这一途径为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。我们的研究结果将提供重要的见解，当mGluR 1-TRPC 3通路异常活跃时，小脑中的分子和细胞过程会出错。我们将研究mGluR 1的新突变，我们已经确定在SCA患者的细胞系，小脑神经细胞和一个新的小鼠模型。这将揭示这些突变如何导致疾病的机制。然后，我们将使用我们已经建立的检测方法来确定可用于治疗SCA的现成且安全的药物。

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.