Sussex Neuroscience

Dr Ruth Murrell-Lagnado

RML

The Association of the Sigma-1 receptor with Motor Neuron Disease

In the central nervous system the Sigma-1 receptor (Sig-1R) has emerged as an important player in regulating neuronal survival and function. It plays a role in the pathophysiology of neuropsychiatric and neurodegenerative disease and has been shown to protect against cerebral damage following an ischemic stroke (1). Mutations in Sig-1R cause inherited juvenile amyotrophic lateral sclerosis (ALS16), a progressive neurodegenerative disease affecting motor neurons that leads to death within a few years (2). Although the mechanisms contributing to the selective death of motor neurons are poorly understood, a disruption of calcium homeostasis is thought to be a critical factor. The aim of this project is to investigate how Sig-1R regulation of calcium signalling between the endoplasmic reticulum (ER) and mitochondria and between the ER and plasma membrane protects motor neurons from dying and whether Sig-1R might be a useful therapeutic target in slowing progression of the disease. The approach will be multidisciplinary. The student will learn a number of molecular and cell biological techniques including fluorescence microscopy imaging methods and electrophysiology.

Sig1R is an ER resident membrane protein known to regulate the stability and function of proteins involved in calcium transport at ER-mitochondrial junctions. We recently identified a novel role for this receptor in the regulation of calcium transport at ER-plasma membrane junctions (3). The project will aim to disentangle the effects of Sig-1R at these two membrane junctions and understand the relevance of the pathways that we have identified in cancer cells to the function of Sig-1R in motor neurons. Different isoforms of the key signalling proteins will be knocked down using the siRNA approach and/or CRISPR/Cas9. The aim will also be to characterize the many diverse ligands that target Sig1R (some of which are in clinic) for their ability to up-or down-regulate Sig-1R activity.

Selected publications

(For full list of publications and more details about the lab, please visit: http://www.sussex.ac.uk/lifesci/murrelllagnadolab)

1) Nguyen et al. (2015) Role of Sigma receptors in neurodegenerative disease. Journal of Pharmacological Sciences 127, 17-29.
2) Watanabe et al., (2016) Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. EMBO Mol Med 8: 1421–1437.
3) Srivats, S., Balasuriya, D., Pasche, M., Vistal, G., Edwardson, J. M., Taylor, C. W., and Murrell-Lagnado, R. D. (2016) Sigma1 receptors inhibit store-operated Ca2+ entry by attenuating coupling of STIM1 to Orai1. The Journal of Cell Biology 213, 65-79. DOI: 10.1083/jcb.201506022