Kevin Barnham

The Barnham laboratory’s focus is on the neurodegenerative diseases, Alzheimer's disease, prion disease and Parkinson's disease, seeking to characterize the molecular events leading to disease pathology, that is delineate the chemical events associated with degeneration. Characterization of these events will enable the identification of potential drug targets.

Key research areas

Structural biology of the neurodegenerative diseases.

The neurodegenerative diseases are characterized by structural transitions to key proteins (Aβ in Alzheimer's disease, a-synuclein in Parkinson's disease and the prion protein in Creutzfeldt-Jakob disease) leading to protein aggregation and a gain of toxic function. The aim of this project is to characterize the structural transitions and early events on the oligomerisation pathway leading to protein aggregation as these correlate with neurotoxicity.

Metallobiology of the neurodegenerative diseases.

Aβ and its precursor, the amyloid precursor protein, α-synuclein and the prion protein interact with metal ions. These interactions have profound effects on protein structure and function. One consequence of the metal binding is the generation of reactive oxygen species which may be responsible for the oxidative stress associated with the neurodegenerative diseases. The aim of this project is to characterize the nature of metal coordination to the various target proteins and investigate the redox chemistry that results.

Membrane biology of the neurodegenerative diseases.

Many of the proteins associated with the neurodegenerative diseases are membrane associated. The interactions between these proteins and lipid membranes influence protein structure and function. The neurotoxicity of Aβ , a-synuclein and the prion protein may be mediated though membrane interactions via lipid peroxidation or a destabilization of membrane integrity. The aim of this project is to characterize the nature of the protein/lipid membrane interactions.

Medicinal Chemistry.

Knowledge gained from the mechanistic studies allows the identification of potential drug targets, and the development of assays that can be used for the selection and improved design of potential therapeutic and diagnostic agents targeting the neurodegenerative diseases. Potential drugs are then synthesized in-house or in collaboration with Prana Biotechnology.

Objectives

• To develop therapeutic and diagnostic strategies targeting the neurodegenerative diseases
• Understand the mechanism(s) leading to neurodegeneration
• Identify novel targets
• Develop assays suitable for drug screening
• Design and synthesize novel molecules as potential therapeutics/diagnostics

Recent Achievements

• Determining the structure of the copper binding domain of APP
• Characterization of the neurotoxic properties of oxidatively modified Aβ.
• Elucidating the role that tyrosine 10 plays in the redox chemistry of Aβ .
• Identifying Aβ /membrane interactions as being a significant modulator of Aβ toxicity.

Techniques

• Biophysics/Spectroscopy: including NMR (protein structure), CD, fluorescence, EPR
• Chemistry: Synthesis (organic and metallo) and mechanistic studies;

Collaborations

Departmental

Ashley Bush; Roberto Cappai; Robert Cherny, Stephen Collins; Colin Masters, Anthony White

University

Andrew Hill (Biochemistry); Frances Separovic (Chemistry)

External

John Wade (HFI), Stephen Bottomley (Monash), Cyril Curtain (Monash)

Funding

• NH&MRC Program Grant:
• NH& MRC RD Wright Fellowship;
• Prana Biotechnology

Recent Publications

Barnham, K.J., McKinstry, W.J., Multhaup, G., Galatis, D., Morton, C.J., Curtain, C.C., Williamson, N.A., White, A.R., Hinds, M.G., Norton, R.S., Beyreuther, K., Masters, C.L., Parker, M.W., Cappai, R. Structure of the Alzheimer’s disease amyloid precursor protein copper binding domain: a regulator of neuronal copper homeostasis. J. Biol. Chem. 2003 ; 278: 17401-17407

Barnham, K.J., Ciccotosto, G.D., Tickler, A.K., Ali, F.E., Smith, D.G., Williamson, N.A., Lam. Y-H., Carrington D., Tew, D., Kocak, G., Volitakis, I., Separovic, F., Barrow, C.J, Wade, J.D., Masters, C.L., Cherny, R.A., Curtain, C.C., Bush, A.I., Cappai, R. Neurotoxic, redox-competent Alzheimer’s β-amyloid is released from lipid membrane by methionine oxidation. J. Biol. Chem. 2003, 278, 42959-42966

Barnham, K.J., Haeffner, F., Ciccotosto, G.D., Curtain, C.C., Tew, D., Mavros, C., Beyreuther, K., Carrington, D., Masters, C.L., Cherny, R.A., Cappai, R., Bush, A.I. Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer’s disease β-amyloid. FASEB J. 2004 , doi:10.1096/fj.04-1890fj6e . FASEB J express2004: 18, 1427-1429

Ciccotosto, G.D., Tew, D., Curtain, C.C, Smith, D., Carrington, D., Masters, C.L., Bush, A.I., Cherny, R.A., Cappai, R., Barnham, K.J. Enhanced toxicity and cellular binding of a modified Amyloid β Peptide with a methionine to valine substitution. J. Biol. Chem. 2004 , 279, 42528-42534

Barnham, K.J. , Masters, C.L., Bush, A.I. Neurodegenerative diseases and oxidative stress. Nature Rev. Drug Disc.,2004 , 3, 205-214

Tickler A.K., Smith D.G., Ciccotosto G.D., Tew D.J., Curtain C.C., Carrington D., Masters C.L., Bush A.I., Cherny R.A., Cappai R., Wade J.D., Barnham K.J. Methylation of the imidazole sidechains of the Alzheimer’s disease amyloid - β peptide results in abolition of SOD-like structures and inhibition of neurotoxicity. J Biol Chem2005, 280, 13355–13363.