Faculty of Medicine,Dentistry and Health Sciences Department of Pathology

White Laboratory

Contact: Associate Professor Anthony White
Phone: +61 3 8344 1805
Fax: +61 3 8344 4004
Email: arwhite@unimelb.edu.au

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.



Recent Achievements




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).

International Collaborators:

Dr Takashi Nonaka (Tokyo Institute of Psychiatry, Japan), Prof. Jari Koistinaho (Eastern Finland University)


Recent Publications

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