Primary supervisor: Dr Judith Sleeman
Other supervisors: Dr Ilary Allodi
Location: University of St Andrews
Project description
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.
References
Condensation properties of stress granules and processing bodies are compromised in myotonic dystrophy type 1. Gulyurtlu S, Magon MS, Guest P, Papavasiliou PP, Morrison KD, Prescott AR, Sleeman JE. Dis Model Mech. 2022 Jul 1;15(7):dmm049294. doi: 10.1242/dmm.049294. Epub 2022 Aug 2. PMID: 35642886
The Cajal body and the nucleolus: "In a relationship" or "It's complicated"? Trinkle-Mulcahy L, Sleeman JE. RNA Biol. 2017 Jun 3;14(6):739-751. doi: 10.1080/15476286.2016.1236169. Epub 2016 Sep 23. PMID: 27661468
Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS. Mora, S., Stuckert, A., von Huth Friis, R., Pietersz, K., Noes-Holt, G., Montañana-Rosell, R., Wang, H., Sørensen, A. T., Selvan, R., Verhaagen, J. & Allodi, I., 7 Jun 2024, In: Nature Communications. 15, 1, 4867.
Locomotor deficits in a mouse model of ALS are paralleled by loss of V1-interneuron connections onto fast motor neurons. Allodi, I., Montañana-Rosell, R., Selvan, R., Löw, P. & Kiehn, O., 31 May 2021, In: Nature Communications. 12, 18 p., 3251.
Suitable first degree subjects
Cell biology, neuroscience, molecular biology
Essential/desirable skills and experience
Desirable: mammalian cell culture, microscopy, image analysis, mouse handling, molecular biology, coding
