Glycosphingolipid recycling in health and disease: the GALC-SapA lipid processing complex

神经退行性疾病，如阿尔茨海默氏症和帕金森氏症，影响了我们老龄人口的很大一部分。不太为人所知的是致命的早发性神经退行性疾病，如Krabbe病，主要影响幼儿。最近的研究表明，导致这些严重但罕见的疾病的突变也与发展迟发性神经肌肉和神经退行性疾病的风险增加有关，包括帕金森病等常见疾病。这一观察结果进一步表明，通过研究罕见疾病，我们可以深入了解影响许多人的许多疾病。我们知道，几种早发性神经退行性疾病的发生是由于构成我们细胞膜的细胞成分（称为脂质）的再循环缺陷。未加工脂质的积累导致细胞损伤和细胞死亡。为了正确处理这些脂质，我们的细胞需要特定的酶和它们的“助手”或激活伴侣。我们的研究集中在酶GALC及其伴侣蛋白SapA上。这些蛋白质中的任何一种的缺陷都会导致克拉布病，并与开角型青光眼（年龄相关性失明的主要原因之一）和运动神经元疾病有关。虽然已知这些酶的突变会导致疾病，但尚不清楚如何引起疾病。我们的工作旨在了解这些酶和激活剂之间的相互作用，以及它们如何共同作用以正确处理细胞中的脂质。通过了解这种机制，我们可以找到新的方法来开发新的治疗方法，不仅针对克拉贝病等早发性疾病，还针对更常见的迟发性神经退行性疾病。

Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases affect a significant proportion of our ageing population. Less well known are the fatal early-onset neurodegenerative diseases such as Krabbe disease that primarily affect young children. Recent research has shown that mutations causing these severe-but-rare diseases are also associated with increased risk of developing late-onset neuromuscular and neurodegenerative disorders, including common ones such as Parkinson's disease. This observation reinforces that by studying rare diseases we can gain crucial insight into a number of diseases that affect a great many people. We know that several early-onset neurodegenerative diseases occur as a result of defects in the recycling of components of the cell known as lipids that make up our cellular membranes. Accumulation of unprocessed lipid results in cellular damage and cell death. In order to correctly process these lipids our cells require specific enzymes and their "helper" or activating partners. Our research is focussed on the enzyme GALC and its partner protein SapA. Defects in either of these proteins cause Krabbe disease and are implicated in open angle glaucoma, one of the leading causes of age-related blindness, and motor neuron disease. Although it is known that mutations in these enzymes cause disease it is not understood how. Our work aims to understand the interactions between these enzymes and activators and how they work together to correctly process lipids in the cell. By understanding this mechanism we can identify new ways to develop novel therapeutics not just for the early-onset diseases such as Krabbe disease but also for the more common late-onset neurodegenerative disorders.