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

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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.