|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
- Donnelly PS, Liddell JR, Lim SC, Paterson BM, Cater MA, Savva MS, Mot AI, James JL, Trounce IA, White AR, Crouch PJ. An impaired mitochondrial electron transport chain increases cellular retention of the hypoxia imaging agent CuII(atsm). Proc. Natl Acad. Sci. USA 2011 Jan 3;109(1):47-52.
- CuII(atsm) protects against peroxynitrite-induced nitrosative damage and prolongs survival in an amyotrophic lateral sclerosis mouse model. Soon CP, Donnelly PS, Turner BJ, Hung LW, Crouch PJ, Sherratt NA, Tan JL, Lim NK, Lam L, Bica L, Lim S, Hickey JL, Morizzi J, Powell A, Finkelstein DI, Culvenor JG, Masters CL, Duce J, White AR, Barnham KJ, Li QX. Journal of Biological Chemistry 2011 Dec 23;286(51):44035-44.
- Subcellular localization of a fluorescent derivative of Cu(II)(atsm) offers insight into the neuroprotective action of Cu(II)(atsm). Price KA, Crouch PJ, Lim S, Paterson BM, Liddell JR, Donnelly PS, White AR. Metallomics 2011 Dec;3(12):1280-90.
- C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress. Meyerowitz J, Parker SJ, Vella LJ, Ng DCh, Price KA, Liddell JR, Caragounis A, Li QX, Masters CL, Nonaka T, Hasegawa M, Bogoyevitch MA, Kanninen KM, Crouch PJ, White AR. Molecular Neurodegeneration 2011 Aug 8;6:57.
- The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. Crouch PJ, Savva MS, Hung LW, Donnelly PS, Mot AI, Parker SJ, Greenough MA, Volitakis I, Adlard PA, Cherny RA, Masters CL, Bush AI, Barnham KJ, White AR. Journal of Neurochemistry 2011 Oct;119(1):220-230.
- Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer's disease. Adlard PA, Bica L, White AR, Nurjono M, Filiz G, Crouch PJ, Donnelly PS, Cappai R, Finkelstein DI, Bush AI. PLoS One 2011 Mar 11;6(3):e17669.
- Sustained activation of glial cell epidermal growth factor receptor by bis(thiosemicarbazonato) metal complexes is associated with inhibition of protein tyrosine phosphatase activity. Price KA, Caragounis A, Paterson BM, Filiz G, Volitakis I, Masters CL, Barnham KJ, Donnelly PS, Crouch PJ, White AR. Journal of Medicinal Chemistry 2009 Nov 12;52(21):6606-20.
- Metallo-complex activation of neuroprotective signalling pathways as a therapeutic treatment for Alzheimer's disease. Bica L, Crouch PJ, Cappai R, White AR. Molecular Biosystems 2009 Feb;5(2):134-42.
- Increasing Cu bioavailability inhibits Abeta oligomers and tau phosphorylation. Crouch PJ, Hung LW, Adlard PA, Cortes M, Lal V, Filiz G, Perez KA, Nurjono M, Caragounis A, Du T, Laughton K, Volitakis I, Bush AI, Li QX, Masters CL, Cappai R, Cherny RA, Donnelly PS, White AR, Barnham KJ. Proceedings of the National Academy of Sciences USA 2009 Jan 13;106(2):381-6.
- Selective intracellular release of copper and zinc ions from bis(thiosemicarbazonato) complexes reduces levels of Alzheimer disease amyloid-beta peptide. Donnelly PS, Caragounis A, Du T, Laughton KM, Volitakis I, Cherny RA, Sharples RA, Hill AF, Li QX, Masters CL, Barnham KJ, White AR. Journal of Biological Chemistry 2008 Feb 22;283(8):4568-77.
- Clioquinol inhibits peroxide-mediated toxicity through up-regulation of phosphoinositol-3-kinase and inhibition of p53 activity. Filiz G, Caragounis A, Bica L, Du T, Masters CL, Crouch PJ, White AR. International Journal of Biochemistry and Cell Biology 2008;40(5):1030-42.
- Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity. White AR, Du T, Laughton KM, Volitakis I, Sharples RA, Xilinas ME, Hoke DE, Holsinger RM, Evin G, Cherny RA, Hill AF, Barnham KJ, Li QX, Bush AI, Masters CL. Journal of Biological Chemistry 2006 Jun 30;281(26):17670-80.
- New frontiers in brain-targeted metal-complexes.
nternational Innovation is the leading global dissemination resource for the wider scientific, technology and research communities, dedicated to disseminating the latest science, research and technological innovations on a global level. More information and a complimentary subscription offer to the publication can be found at: www.researchmedia.eu