|Contact:||Associate Professor Anthony White|
|Phone:||+61 3 8344 1805|
|Fax:||+61 3 8344 4004|
The White laboratory studies the role of biometals such as copper (Cu), zinc (Zn) and iron (Fe) in neurodegenerative diseases. These metals have important roles in normal cell functions. However, abnormal biometal metabolism is central to a number of neurodegenerative illnesses including Alzheimer's disease, Parkinson's disease, motor neuron disease and prion disorders. Recent studies have shown that pharmacological modulation of biometal homeostasis in the brain may offer a novel therapeutic approach to treating these brain diseases. An important step in developing these novel drugs is to obtain a clear understanding of how biometals affect neuronal metabolism and synaptic function. Our laboratory is investigating the role of biometals in neuronal cell signaling pathways. We are also developing and testing novel neuroprotective metallo-complexes that may restore brain function in neurodegenerative diseases.
Key research areas are:
Investigating how biometals control neuronal cell signaling pathways
Biometals are central to the pathology of many brain diseases, however, little is known about the normal function of metals such as Cu and Zn in neuronal cell signaling pathways. These pathways affect neuronal survival and synaptic function and are important targets for therapeutic intervention in neurodegeneration. It is critical to obtain a greater understanding of how biometals modulate cell signaling during normal brain function and in disease. We are currently investigating how Cu and Zn control a number of different cell signaling pathways including PI3K, GSK3 and MAPK pathways and how age-related changes to these pathways contribute to neurodegenerative diseases.
Development of neuroprotective metallo-complexes
Together with collaborators at the Department of Pathology and Bio21 Institute, we have identified a class of neuroprotective cell permeable metallo-complexes (bis(thiosemicarbazonato)-metal complexes or BTSCs). These small molecules cross the blood brain barrier and enter neurons and glia. Delivery of small levels of Cu or Zn can be modulated by structural changes to the complexes. These metallo-compounds offer exciting potential as a novel therapeutic strategy for treating neurodegenerative diseases. Release of the metals activates neuroprotective signaling cascades resulting in significant improvements in multiple animal models of neurodegeneration including Alzheimer’s disease, Parkinson’s disease and motor neuron disease. We are currently using cell culture and animal models to investigate the uptake, metal release and activation of neuroprotective pathways of these important compounds with the aim of moving the compounds into pre-clinical testing for treatment of neurodegeneration.
This project was identified by the National Health and Medical Research Council of Australia (NH&MRC) as one of the Top Ten Research Projects funded in 2010. http://www.nhmrc.gov.au/guidelines/publications/r48
Determining the pathological processes that cause motor neuron disease
Motor neuron disease (MND) is a group of neurodegenerative diseases that affect adults in the prime of their life. This illness results in progressive loss of motor function due to degeneration of upper and lower spinal motor neurons and there is no effective treatment. Although little is known about the disease, recent studies have identified a protein called TDP-43 as a major constituent of aggregates found in neurons of patients with the disease. Aggregation of TDP-43 is believed to be linked to degeneration of motor neurons. Our laboratory has been investigating the early changes associated with abnormal TDP-43 processing and have shown that specific kinases such as JNK are involved in controlling TDP-43 accumulation in RNA stress granules, a precursor to TDP-43 aggregation. Our research is continuing to investigate how neuronal cell stress activates kinase-dependent pathways that control TDP-43 accumulation either through direct phosphorylation of TDP-43 or through modulation of interacting proteins such as hnRNPs. These kinase pathways may offer new drug target opportunities for therapeutic intervention.
Identifying new disease pathways in childhood neurodegeneration (Batten disease)
Neuronal ceroid lipofuscinosis (NCL or Batten disease) is the most common group of fatal neurodegenerative disorders of childhood. The disease is caused by mutation of one of several identified genes associated with the endoplasmic reticulum or lysosome and results in neuronal degeneration characterized by vision impairment, motor and cognitive dysfunction, seizures and is always fatal. Very little is known about the underlying molecular processes that result in neuronal degeneration. Together with collaborators in New Zealand and Sydney, we are investigating how mutation of the CLN6 gene results in abnormal zinc metabolism and aberrant cell signaling. The mapping of these abnormal molecular processes may lead to a greater understanding of CLN6 pathology and potentially further our understanding of other forms of Batten disease.
- Identifying and characterizing novel biometal-mediated cell signaling pathways involved in neurodegenerative diseases.
- Development of metallo-complexes as a broad neuroprotective compound for treatment of neurodegenerative diseases.
- Understand the molecular pathways leading to development of motor neuron disease in adults and Batten disease in children and infants.
- Development of bis(thiosemicarbazone)metal complexes as neuroprotective agents.
- Delineating the molecular pathways underlying the protective action of metallo-complexes in neurons.
- Identifying a key role for specific kinases in controlling accumulation of TDP-43 in neurons during stress.
- Cell culture
- Protein chemistry
- Molecular biology
- Animal behavior (motor and cognition testing)
- Structure-activity relationship studies on metallo-complexes
Dr Peter Crouch, Prof. Roberto Cappai, Assoc. Prof. Steven Collins.
Assoc. Prof. Kevin Barnham (Pharmacology), Dr Paul Donnelly (Chemistry), Prof. James Camakaris (Genetics), Prof. Andrew Hill (Biochemistry and Molecular Biology), Assoc. Prof. Marie Bogoyevitch (Biochemistry and Molecular Biology).
Prof. Colin Masters (MHRI), Prof. Ashley Bush (MHRI), Assoc. Prof. David Finkelstein (MHRI), Assoc. Prof. Robert Cherny (MHRI), Dr Paul Adlard (MHRI), Dr Sharon La Fontaine (Deakin University), Dr Damien Keating (Flinders University), Imke Tammen, (University of Sydney).
Dr Takashi Nonaka (Tokyo Institute of Psychiatry, Japan), Prof. Jari Koistinaho (Eastern Finland University)
- NHMRC Program Grant
- NHMRC Project grant
- ARC Future Fellowship
- ARC Discovery grant
- Brain Foundation
- Motor Neurone Disease Research Institute of Australia
- Bethlehem Griffiths Research Foundation
- CASS Foundation
- Alzheimer’s Australia
- Grubman, A., James, S.A., James, J., Duncan, C., Volitakis, I., Hickey, J.L., Crouch, P.J., Donnelly P.S., Kanninen K.M., Liddell, J.R., Cotman, S.L., de Jonge, M.D., and White, A.R. X-ray fluorescence imaging reveals subcellular biometal disturbances in a childhood neurodegenerative disorder. Chemical Science (2014) 5, 2503 - 2516.
- Roberts, B., Lim, N., McAllum, E., Donnelly, P., Hare, D., Doble, P., Turner, B., Price, K., Lim, S-C., Paterson, B., Hickey, J., Rhoads, T., Williams, J., Kanninen, K., Hung, L., Liddell, J., Grubman, A., Monty, J., Llanos, R., Kramer, D., Mercer, J., Bush, A., Masters, C., Duce, J., Li, Q-X., Beckman, J., Barnham, K., White, A.R., and Crouch, P. CuII(atsm) increases mutant SOD1 in vivo but improves mouse locomotor function and survival. Journal of Neuroscience (2014) 4, 8021-31.
- Lim, N., Hung, L.W., Pang, T., McLean, C., Liddell, J.R., Hilton, J., Li, Q-X., White, A.R., Hannan, A., and Crouch, P.J. Localized changes to glycogen synthase kinase-3 and collapsing response mediator protein-2 in the Huntington’s disease affected brain. Human Molecular Genetics (2014) 23, 4051-63.
- Grubman, A. and White, A.R. Copper as a key regulator of cell signaling pathways. Expert Reviews in Molecular Medicine (2014) May 22;16:e11. doi: 10.1017/erm.2014.11.
- Grubman, A., Pollari, E., Duncan, C., Caragounis, A., Blom, T., Volitakis, I., Wong, A., Cooper, J., Crouch, P.J., Koistinaho, J., Jalanko, A., White, A.R., Kanninen, K.M. Deregulation of biometal homeostasis: the missing link for neuronal ceroid lipofuscinoses? Metallomics (2014) 6, 932-493.
- Acevedo, K.M., Opazo Martinez, C.R., Norrish, D., Challis, L.M., Li, Q-X., White, A.R., Bush, A.I., and Camakaris. J. Threonine-668 phosphorylation of Amyloid Precursor Protein is essential for its copper-responsive trafficking. Journal of Biological Chemistry (2014) 289, 11007-11019.
- Kanninen, K.M., Grubman, A., Caragounis, A., Duncan, D., Parker, S.J., Lidgerwood, G.E., Volitakis, V., Ganio, G., Crouch, P.J. and White, A.R. Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis. Biology Open (2013) 2, 635-646.
- Duncan, C., Bica, L., Crouch, P.J., Caragounis, A., Lidgerwood, G.E., Parker, S.J., Meyerowitz, J., Volitakis, I., Liddell, J.R., Raghupathi, R., Paterson, B.M., Duffield, M.D., Cappai, R., Donnelly, P.S., Grubman, A., Camakaris, J., Keating, D.J., White, A.R. Copper modulates the large dense core vesicle secretory pathway in PC12 cells. Metallomics (2013) 5(6):700-14.
- Hare, D.J., Grubman, A., Ryan, T.M., Lothian, A., Liddell, J.R., Grimm, R. Matsuda, T., Doble, P.A., Cherny, R.A., Bush, A.I., White, A.R., Masters, C.L., Roberts, B.R. Profiling the iron, copper and zinc content in primary neuron and astrocyte cultures by rapid online quantitative size exclusion chromatography-inductively coupled plasma-mass spectrometry. Metallomics (2013) 5, 1656-62.
- Liddell, J.R., Obando, D., Liu, J., Ganio, G., Volitakis, I., Mok, S., Crouch, P.J., Codd, R. and White, A.R. Lipophilic adamantyl- or deferasirox-based conjugates of desferrioxamine B have enhanced neuroprotective capacity: Implications for Parkinson's disease. Free Radical Biology and Medicine. (2013) 60, 147-156.
- Donnelly, P.S., Liddell, J.R., Lim, S.C., Paterson, B.M., Cater, M.A., Savva, M.S., Mot, A.I., James, J.L., Trounce, I.A., White, A.R., Crouch, P.J. An impaired mitochondrial electron transport chain increases cellular retention of the hypoxia imaging agent CuII(atsm). Proc. Natl Acad. Sci. USA (2012) 109:47-52.
- Hung, L.W., Villemagne, V.L. Cheng, L., Sherratt, N.A., Ayton, S., White, A.R., Crouch, P.J., Lim, S.C., Leong, S.L., Wilkins, S George, J., Roberts, B., Pham, C.L., Chiu, F.C.K., Shakelford, D.M. Powell, A.K., Masters, C.L., Bush, A.I. O’Keefe, G. Culvenor, J.G., Cappai, R. Cherny, R.A., Donnelly, P.S., Hill, A.F., Finkelstein, D.I., Barnham. K.J. The hypoxia imaging agent, CuII(atsm), is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson’s disease. J. Exp. Med.(2012) 209, 837-54.
- Schieber, C. Bestetti, A. Lim, J. P., Ryan, A., Nguyen, T-L., Eldridge, R. White, A. R., Gleeson, P. A., Donnelly, P. S., Williams, S. J., and Mulvaney, P. Conjugation of Transferrin to Azide-Modified CdSe/ZnS Core-Shell Quantum Dots using Cyclooctyne Click Chemistry. Angewandte Chemie (2012) 51(42):10523-7.
- Price, K. A., Hickey, J. L., Xiao, Z., Wedd, A. G., James, S. A., Liddell, J. R., Crouch, P. J., Donnelly, P. S. and White, A.R. The challenges of using a copper fluorescent sensor (CS1) to track intracellular distributions of copper in neuronal and glial cells. Chem. Sci., (2012) 3, 2748-2759.
- Crouch, P.J., Hung, L.W., Adlard, P.A., Cortes, M., Lal, V., Filiz, G., Perez, K.A., Nurjono, M., Caragounis, A., Du, T., Laughton, K.M., Volitakis, I., Bush, A.I., Li, Q-X., Masters, C.L., Cappai, R., Cherny, R.A., Donnelly, P.S., Barnham, K.J. and White, A.R. Increasing Cu bio-availability inhibits Ab oligomers and tau phosphorylation. Proc. Natl Acad. Sci. USA (2009) 106, 381-386.
- White, A.R., Enever, P., Tayebi, M., Mushens, R., Linehan, J., Brandner, S., Anstee, D., Collinge, J. and Hawke, S.H. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature (2003) 422, 80-83.
- White, A.R., Multhaup, G., Galatis, D., McKinstry, W.J., Parker, M.W., Pipkorn, R., Beyreuther, K., Masters, C.L. and Cappai, R. Contrasting, Species-Dependent Modulation of Copper-Mediated Neurotoxicity by the Alzheimer’s Disease Amyloid Precursor Protein. The Journal of Neuroscience (2002) 22, 365–376.
- White, A.R., Huang, X., Jobling, M.F., Barrow, C.J., Beyreuther, K., Masters, C.L., Bush, A.I. and Cappai, R. Homocysteine potentiates copper and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer’s-type neurodegenerative pathways. Journal of Neurochemistry (2001) 76, 1509-1520.
- White, A.R., Maher, F., Multhaup, G., Bellingham, S., Camakaris, J., Zheng, H., Bush, A. I., Beyreuther, K., Masters, C.L. and Cappai, R. The Alzheimer’s amyloid precursor protein modulates copper-induced toxicity and oxidative stress in primary neuronal cultures. Journal of Neuroscience (1999) 19, 9170-9179.
- White, A.R., Reyes, R., Mercer, J.F.B., Camakaris, J., Zheng, H., Bush, A.I., Multhaup, G., Beyreuther, K., Masters, C.L. and Cappai, R. Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain Research (1999) 842, 439-444.