|Contact:||Dr Janetta Culvenor|
|Phone:||+61 3 8344 3991|
|Fax:||+61 3 8344 4004|
Major Research Focus
The Culvenor Laboratory is focused on elucidating key mechanisms causing Alzheimer's and Parkinson's disease as well as the associated Dementia with Lewy bodies disorder. Recently identified genetically linked proteins are investigated for their dysfunction in disease.
This involves antibody generation and characterisation, protein biochemistry, molecular biology, enzymology, assay development, cell culture, animal modelling and microscopy. This provides important clues to understanding the disease process for these common neurodegenerative brain disorders to uncover strategies to delay disease onset in the design of therapeutics.
Since 1997 mutations in several genes have been shown to cause recessive or dominantly inherited Parkinson's disease. Parkinson's disease is the most common movement disorder affecting the aged and the second most common neurodegenerative disease. It is a progressive brain disorder with clinical characteristics of tremor and rigidity caused by loss of neurons and reduced dopamine neurotransmitter levels. A major pathological feature is the abnormal intracellular aggregation of alpha-synuclein fibrillar protein to form inclusions termed Lewy bodies. Our current work involves investigation of the Parkinson's-associated kinase proteins Leucine-rich repeat kinase 2 and the PTEN-induced kinase 1.
The department of Biochemistry and Molecular Biology at the Bio21 Molecular Science and Biotechnology Institute.
The Mental Health Research Institute of Victoria.
Major Research Areas
1. Development of Improved Mouse Models of Parkinson's Disease and Dementia with Lewy Bodies.
2. Investigation of regulation and target substrates for Parkinson's disease mitochondrial kinase PTEN-induced kinase 1.
Supported by Michael J.Fox Foundation for Parkinson's disease Rapid Response and Innovation Award in 2007 and 2008 and by an NHMRC project grant 2009-2011.
3. Deciphering the biochemical properties of Parkinson's disease-associated Leucine-rich Repeat Kinase 2.
Enzymes provide ideal candidate sites for therapeutic disease intervention. This LRRK2 work was supported by a priming project grant from the Australian Brain Foundation for 2008, and will be continued with support by a major three year project grant from the NHMRC for 2009 -2011.
Domain Structure of LRRK2 protein kinase with site of common G2019S mutation shown.
- Australian NHMRC
- Bethlehem Griffiths Research Foundation
- Australian Brain Foundation
- US Michael J. Fox Foundation for Parkinson's Research
- J.A. Duncan and D.R. Stuart Trust Funds
- The University of Melbourne
- ANZ Trusts
- Potter Foundation
- Assoc. Prof. Heung-Chin Cheng, Department of Biochemistry and Molecular Biology, The University of Melbourne
- Dr. Kipros Gabriel, Department of Biochemistry, Monash University
- Dr. Genevieve Evin, Dr. Qiao-Xin Li, Dr. Anthony White, Assoc. Prof. Roberto Cappai from the Department of Pathology, University of Melbourne
- D. Terrence Mulhern, Dr. Nichlolas Williamson, Department of Biochemistry and Molecular Biology, The University of Melbourne
- Dr Paul Lockhart, Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Melbourne, Australia
- Dr Javier Sáez-Valero, Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Alicante, Spain
- Professor Virginia Lee, University of Pennsylvania, Pennsylvania, USA
- Professor Malcolm Horne, The Howard Florey Institute
- Prof. Catriona McLean, Alfred Hospital, Vic.
- Assoc. Prof. Maarten van den Buuse, Dr. David Finkelstein, Dr. Robert Cherny, Assoc. Prof. Ashley Bush, and Prof. Colin Masters from the Mental Health Research Institute of Victoria
- Hung LW, Villemagne VL, Cheng L, Sheratt NA, Ayton S, White AR, Crouch PJ, Lim S, Leong SL, Wilkins S, George J, Roberts B, Pham CL, Chiu FCK, Shackleford DM, Powell AK, Masters CL, Bush AI, O'Keefe G, Culvenor JG, Cappai R, Cherny RA, Donnelly PS, Hill AF, Finkelstein DI, Barnham KJ 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 accepted Feb 2012
-Soon CP, Donnelly PS, Turner BJ, Hung LW, Crouch PJ, Sherratt NA, Tan JL, Lim NK, Lam L, Bica L, Culvenor JG et al: CUII(ATSM) protects against peroxynitrite-induced nitrosative damage and prolongs survival in an amyotrophic lateral sclerosis mouse model. J Biol Chem 286(51):44035-44. Epub 2011 Oct 27.
-Silveyra, M.-X., Garcia-Ayllon, M.-S., Serra-Basante, C., Mazzoni, V., Garcia-Gutierrez, M.-S., Manzanares, J., CULVENOR, J.G. and Saez-Valero, J. (2011) Changes in acetylcholinesterase expression are associated with altered presenilin-1 levels. Neurobiol Aging accepted 6 April.
- Ia, K.K., Jeschke, G.R., Deng, Y., Kamaruddin, M.A., Williamson, N.A., Scanlon, D.B., CULVENOR, J.G., Hossain, M.I., Purcell, A.W., Liu, S., Zhu, H.J., Catimel, B., Turk, B.E. and Cheng, H.C. (2011) Defining the substrate specificity determinants recognized by the active site of C-Terminal Src Kinase-Homologous Kinase (CHK) and identification of β-Synuclein as a potential CHK physiological substrate. Biochemistry, 50, 6667-6677
- Cheng, H.C., Johnson, T.M., Mills, R.D., Chong, Y.P., Chan, K.C. and CULVENOR, J.G. (2010) Allosteric networks governing regulation and catalysis of Src-family protein tyrosine kinases-implications for disease-associated kinases. Clin Exp Pharmacol Physiol 37, 93-101.
- George, S. Mok, S.S., Nurjono, M., Ayton, S., Finkelstein, D.I., Masters, C.L., Li, Q.-X. and CULVENOR, J.G. (2010) a-Synuclein transgenic mice reveal compensatory increases in Parkinson's Disease-associated proteins DJ-1 and Parkin and have enhanced a-synuclein and PINK1 levels after rotenone treatment. J. Mol. Neurosci. 42, 243-254.
- Foo, J.H., CULVENOR, J.G., Ferrero, R.L., Kwok, T., Lithgow, T. and Gabriel, K. (2010)
Both the p33 and p55 Subunits of the Helicobacter pylori vacuolating VacA are targeted to mammalian mitochondria. J. Mol. Biol. 401, 792-798.
-Ho, H., Hoke, D.E., Chua, Y.J., CULVENOR, J.G., Masters, C., White, A.R. and Evin, G. (2010) Effect of metal chelators on γ-secretase indicates that calcium and magnesium ions facilitate cleavage of Alzheimer amyloid precursor substrate. Int J Alzheimers Dis. Dec 28, 950932.
-Tinsley, R.B., Bye, C., Tziotis-Vais, A., Parish, C.L., George, S., CULVENOR, J.G., Li, Q.-X., Masters, C.L., Finkelstein, D.I., and Horne, M.K. (2009) Dopamine D2 receptor knockout mice develop features of Parkinson’s disease. Annals Neurol. 66, 472-484.
-Smidt, K., Jessen, N., Petersen, A.B., Larsen, A., Magnusson, N., Jeppesen, J.B., Stoltenberg, M., CULVENOR, J.G., Tsatsanis, A., Brock, B., Schmitz, O., Wogensen, L., Bush, A.I. and Rungby, J. (2009) SLC30A3 responds to glucose- and zinc variations in ß-cells and is critical for insulin production and in vivo glucose-metabolism during ß-cell stress. PLoS ONE 25;4(5):e5684.
- Hung, Y.H., Robb, E.L., Volitakis, I., Ho, M., Evin, G., Li, Q.-X., CULVENOR, J.G., Masters CL, Cherny R.A. and Bush, A.I. (2009) Paradoxical condensation of copper with elevated beta-amyloid in lipid rafts under cellular copper deficiency conditions: implications for Alzheimer disease. J. Biol. Chem. 284, 21899-21907.
Dutescu, R.M., Li, Q.-X., Crowston, J., Masters, C.L., Baird, P.N., and CULVENOR, J.G. (2009) Amyloid precursor protein processing and retinal pathology in Alzheimer’s disease mouse models.Graefe’s Arch. for Clin. Exp. Opthalmology 247, 1213-1221.
- Mills, R.D., Sim, C.H., Mulhern, T.D., CULVENOR, J.G. and Cheng, H.-C. (2008) Biochemical aspects of the neuprotective mechanism of PTEN-induced kinase-1 (PINK1) J. Neurochem. 105, 18-33.
- George, S., Van den Buuse, M., Mok, S.S., Masters, C.L., Li, Q.-X., and CULVENOR, J. G. (2008) Alpha-Synuclein transgenic mice exhibit reduced anxiety-like behaviour. Exp. Neurol. 210: 788-792- Silveyra, M.-X., Evin, G., Montenegro, M.-F., Vidal, C.J., Martínez, S., CULVENOR, J.G., and Sáez-Valero, J. (2008) Presenilin-1 interacts with acetylcholinesterase and alters its enzymatic activity and glycosylation. Mol. Cell Biol. 210, 788-792.