Linking SMA and ALS through post-translational modifications of cellular proteins

The Sleeman group is interested in the molecular and cellular mechanisms that lead to symptoms in the inherited motor neurone disease, Spinal Muscular Atrophy (SMA). It is increasingly apparent that there are common mechanisms at play in SMA and Amyotrophic Lateral Sclerosis (ALS or classical Motor Neurone Disease). We use a range of interdisciplinary approaches, including cell biology, live cell microscopy, quantitative proteomics and electrophysiology to answer our research questions. This is achieved through collaboration with experts here in St Andrews and at the Universities of Edinburgh and Aberdeen.

There is an increasing appreciation of potential links between SMA (Spinal Muscular Atrophy) and ALS (Amyotrophic Lateral Sclerosis) at the molecular level. Proteins such as FUS and TDP43/TARDBP, implicated in ALS pathology share a number of features with the SMN (survival motor neurons) protein, which is deficient in SMA. Each has multiple roles within cells, localizing both to the nucleus and to the cytoplasm and each has been found in phase-separated sub-cellular structures whose existence is proposed to increase local concentrations of proteins and RNAs, contributing to the efficiency of cellular processes. Using microscopy and proteomics, we have recently uncovered changes in post-translational modifications of key proteins in cell-culture models of ALS, which have the potential to impact on cellular pathways involved in SMA pathology. This project will use a combination of protein analysis, fixed and live cell microscopy, electrophysiology of human iPSC-derived motor neurones and analysis of of whole-animal models of both SMA and ALS to investigate this intersection further. The combination of molecular, cell culture and functional techniques provides a unique opportunity to search for similarities at the molecular level that may be of pathological relevance for both conditions.