The importance of membrane-less organelles in the nucleus and cytoplasm is becoming increasingly apparent in motor neuron (MN) disease pathology. For example, nuclear gems and Cajal bodies are disrupted in the childhood motor neuron disease spinal muscular atrophy, while the stabilisation of cytoplasmic accumulations of the TDP43 protein is characteristic of most sporadic and familial Amyotrophic Lateral Sclerosis (ALS) cases.
Membrane-less organelles are formed by a biophysical process called liquid-liquid phase separation (LLPS), which depends on weak transient interactions between proteins and RNA species. LLPS regulation remains poorly understood, but it is influenced by post-translational modification (PTM) of proteins found in membrane-less organelles. By using cell culture systems, including induced pluripotent stem cells (iPSCs), we have shown that inhibiting specific PTMs of proteins during MN differentiation can cause functional defects that mimic those seen in MNs derived from ALS patients. Importantly, upregulating the same PTMs can also partially correct functional defects seen in patient cells.
In this project, we will extend these studies to further investigate the protective mechanisms combining cell culture models of various types of ALS, and gene therapy approaches targeting PTMs in multiple ALS mouse models. AAV-PHP.eBs allow for systemic delivery of gene therapy upon intravenous administration. Motor functions of treated mice will be investigated using computational behavioural analysis.
How to apply
For more information please see here: Modulating post translational modifications as a therapeutic strategy for ALS | The Euan MacDonald Centre