Project - Is nerve cell death in amyotrophic lateral sclerosis (ALS) triggered by copper deficiency?
Research Project Abstract
In some forms of inherited ALS the cellular protein superoxide dismutase 1 (SOD1) is abnormal, resulting in the selective death of motor nerves, which are essential for life. It is unknown how the protein is actually altered in human disease, and why these changes cause the death of only these critical nerve cells. This project takes a fresh perspective, using cutting-edge analytical technologies on ALS patient samples, to understand how SOD1 protein changes contribute to the death of motor nerves. Understanding why these, but not all nerve cells, die in ALS will accelerate the development of therapies that prevent nerve cell death.
List all Chief investigators and associate investigators
- CIA: Professor Kay Double, The University of Sydney
- CIB: Associate Professor Dominic Hare, The University of Melbourne
- CIC: Professor Stuart Cordwell, The University of Sydney
- CID: Dr Benjamin Trist, The University of Sydney
- Professional staff: Dr Fabian Kreilaus, The University of Sydney
- Professional staff: Ms Veronica Cottam, The University of Sydney
- Research students: Mr Amr Abdeen, The University of Sydney
Challenges within the field
Amyotrophic lateral sclerosis (ALS) involves the progressive death of nerve cells in the brain and spinal cord that control movement. The reason for the death of these cells is unknown, and there are currently no therapies available which slow or halt the death of these nerve cells. Nerve cell death likely results from a number of interrelated factors. Identifying key disease mechanisms that occur early in the disease process and drive the progression of the disease will enable us to develop therapies capable of slowing or preventing nerve cell death.
Research Project Description
Without a better understanding of the molecular mechanisms underlying nerve cell vulnerability, ALS will remain an incurable disorder.
Abnormalities in a protein called superoxide dismutase 1 (SOD1) have been linked to nerve cell death in ALS patients for over two decades. Data from a range of model systems show that mutations in the gene encoding SOD1, as well as chemical alterations to the protein itself, disrupt the normal functioning of the protein and cause it to become toxic to nerve cells. Conversely, removing or correcting abnormal SOD1 protein reduces nerve cell death and improves motor function in models ystems. There is little data, however, to show that these same changes to SOD1 are present in ALS patients. Such data would greatly improve our understanding of the disease process. Here we are using advanced analytical techniques to identify changes to SOD1 protein in human ALS patient tissues and biofluids. Data from this study will improve our understanding of the human disease and support the development of effective therapies for this disorder.
Approaches we are using in this project include neuropathology, studying the interactions between protein and metals using several types of mass spectroscopy and synchrotron technologies, determining levels of total and subtypes of proteins using protein isolation and quantification using gel electrophoresis and post-mortem human brain studies.
Funding for this work
MND Australia Innovator grant: Validating molecular pathways of SOD1 toxicity in human ALS.
Research Objectives
- To identify pathways leading to the death of motor neurons in ALS.
- To identify key points within those pathways that represent targets for the development of treatments capable of slowing or halting neuron death.
Key Publications from this project
- Trist B, Hilton JB, Crouch PJ, Hare DJ, Double KL. (2020) Superoxide dismutase 1 in health and disease: How a front-line antioxidant becomes neurotoxic. Angew. Chem. Int. Ed. 59, 2-34. doi: 10.1002/anie.202000451.
- Trist, B.G., Hare, D.J., Double, K.L. (2018) A proposed mechanism for neurodegeneration in movement disorders characterized by metal dyshomeostasis and oxidative stress. Cell Chem Bio. 25(7):807-816. doi:10.1016/j.chembiol.2018.05.004.
- Trist, B.G., Davies, K.M., Cottam, V., Genoud, S., Ortega, R., Roudeau, S., Carmona, A., De Silva, K., Wasigner, V., Lewis, S.J.G., Sachdev, P., Smith, B., Troakes, C., Vance, C., Shaw, C., Al-Sarraj, S., Ball, H., Halliday, G., Hare, D.J., Double, K.L. (2017) Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson’s disease brain. Acta Neuropathol. 134(1):113-127. doi:10.1007/s00401-017-1726-6
Infographic / Medical Diagram / Scientific Diagram / Picture
Key Findings
- We find that SOD1 protein is abnormal within vulnerable nerve cells in the spinal cords of ALS patients. We have discovered that in ALS patients SOD1 protein exists in an immature, disordered structure which is less enzymatically active compared with that in healthy individuals. The abnormal protein is present in a different part of the cell than in healthy individuals and has a greater tendency to accumulate in an abnormal, potentially toxic, manner.
- We are exploring why and how SOD1 protein exhibits these features with the aim of uncovering mechanisms to prevent accumulation of abnormal SOD1 in ALS patients.
- Our work constitutes the first comprehensive characterization of this protein in ALS patients.