Professor Kay Double

Professor Kay Double, Professor of Neuroscience, The University of Sydney.

Kay is Professor of Neuroscience at the Brain and Mind Centre at the University of Sydney where she heads the Neurodegeneration Research Laboratory. Her qualifications include a PhD and the international postdoctoral degree of Habilitation in the field of neurochemistry, that is, the biochemistry of the brain in health and disease. Her work identifies cellular pathways responsible for brain cell death in degenerative disorders, including Parkinson’s disease, motor neurone disease, and dementia disorders, and developing and testing treatments to slow or halt the disease process. Her group recently identified a new type of abnormal protein in Parkinson’s disease which is thought to be associated with brain cell damage. She is also developing novel methods to image disease-associated changes in the brain and spinal cord to improve diagnosis and monitor treatment effects. She leads multidisciplinary, international research groups to meet these challenges in a collaborative manner. In addition to her research awards, Kay is an award-winning supervisor of Early Career Researchers and students.

Forefront Group:

  • BMC Neurogeneration Lab Motor Neuron Disease Research Group Leader
  • BMC Neurodegeneration Lab Parkinson's Disease Research Group Leader

Affiliate Organisations

The University of Sydney, The University of Melbourne, University of Technology, Sydney, Neuroscience Research Australia, The University of Würzburg, Germany

Neurodegeneration of interest:

Parkinson’s disease, Motor Neurone Disease, Dementia disorders, Ageing

Expertise:

  • Neurodegeneration research
  • Neuroprotection research
  • Development and validation of neuroimaging technologies
  • Neuroscience teaching at undergraduate and graduate level including research student supervision and teaching research

Specific Skills:

  • Neurochemistry
  • Neuropathology
  • Neuroimaging

Specific Skills:

  • Research student positions are available at Honours, Masters or PhD level for the projects below, please contact Prof Double for details.
  • Is nerve cell death in Parkinson disease and motor neurone disease triggered by copper deficiency? CIA.
  • Developing PET-based neuroimaging for copper in the human central nervous system. CIA.
  • The biology of copper and iron in the healthy and diseased human central nervous system. CIA.
  • Who is teaching tertiary neuroscience in Australia? A survey of skills and experience. Joint CI.

Project - Developing PET-based neuroimaging for copper in the human central nervous system

Research Project Abstract

Copper is a vital but potentially toxic trace element critical for the health and function of neurons. Disorders in which brain copper levels are pathologically low (e.g., Menkes disease) or high (Wilson disease) are characterised by prominent neurological symptoms and are treated with therapies for restoring brain copper levels. Disorders of central nervous system (CNS) copper dyshomeostasis also include more common disorders, such as amyotrophic lateral sclerosis (ALS) and Parkinson disease. Treatments that modify copper levels in the nervous system are significantly hampered by the problem that copper cannot be quantified in the living brain, so that the effectiveness of therapies for restoring CNS copper cannot be measured in patients. Our solution is to develop the first tool to quantify and assess the distribution of copper in the living brain. This outcome would be a significant advance toward using CNS copper as a disease biomarker, and for monitoring the safety and efficacy of treatment of disorders of central copper dyshomeostasis. Our ultimate objective is to provide a PET-based neuroimaging tool for quantifying bioavailable copper in the CNS for clinical use.

List all Chief investigators and associate investigators

  • CIA: Professor Kay Double, The University of Sydney
  • CIB: Professor Elizabeth New, The University of Sydney
  • Professional staff: Dr Benjamin Rowlands, The University of Sydney
  • Professional staff: Ms Veronica Cottam, The University of Sydney

Challenges within the field

Copper is essential for brain health but a range of diseases result from either an excess, or deficiency, of copper. Drugs which restore normal copper levels in the brain are established, or emerging, treatments for these diseases, including the common movement disorder Parkinson’s disease. To achieve safe and effective treatment, it will be essential to measure brain copper levels but such a method does not exist. This project will develop a quantitative imaging technology to measure copper levels in the living brain.

Research Project Description

An inability to measure copper in the living human brain is hammering the development of safe and effective treatments for a range of neurological diseases associated with altered brain copper. We are a team of experts in copper in neurological disease, copper chemistry and neuroimaging and are combining these skills with the aim to develop the first method to quantify copper in the living brain for clinical use. Such a method would improve diagnosis of diseases of copper dyshomeostasis and allow longituninal treatment monitoring to improve clinical benefits for patients.

Approaches used include copper probe design and synthesis, and testing and validating the safety and efficacy of the probe using a variety of in vitro, cell and whole animal-based imaging techniques, including PET imaging and Australia’s only Deep In Vivo Explorer microscope.

Research Objectives

  • To develop a quantitiative neuroimaging method to quantify copper in the mammalian central nervous system.
  • To validate the efficacy and safety of this new tool in mammalian models of altered brain copper.

Key Publications from this project

New project no publ yet

Infographic / Medical Diagram / Scientific Diagram / Picture

Don’t have anything for this yet but can provide it later

Key Findings

  • We have developed a novel small molecule copper-sensing probe that can be used in a variety of imaging platforms. In this new project we will employ a number of imaging modalities with the eventual aim to develop a novel PET-based neuroimaging method to quantify brain copper during life.
  • We are recruiting research students (Honours, Masters or PhD level) to be involved in this work. The project would suit students interested in the biology of metals or in neuroimaging or microscopy.

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.