Culvenor Laboratory
| Contact: | Dr Janetta Culvenor |
|---|---|
| Phone: | +61 3 8344 3990 |
| Fax: | +61 3 8344 4004 |
| Email: | janetta@unimelb.edu.au |
Location
Neurodegeneration Laboratory, Centre for Neuroscience
Lab Staff Members
Head of Laboratory
Dr Janetta G. Culvenor, BSc(Hons), PhD
Research Staff
Dr Tim Johnson, Bsc(Hons), Phd
Gradute Students
Mr Ryan Mills, BSc(Hons)
Mr Chou Hung Sim, Bsc(Hons)
The Neurodegeneration Laboratory established in the Centre in 2001 is focused on elicidating 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.
Affiliated departments
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.
Financial Support
- 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
Collaborators
- Dr Paul Lockhart, Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Melbourne, Australia
- Professor Matthew Farrer, Dr. Heather Melrose & Dr Justus Dachsel, Dept. of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
- Dr Javier Sáez-Valero, Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Alicante, Spain
- Assoc. Prof. Heung-Chin Cheng, Department of Biochemistry and Molecular Biology, The University of Melbourne
- Dr. Kipros Gabriel, Department of Biochemistry, Monash University
- D. Terrence Mulhern, Dr. Nichlolas Williamson, Department of Biochemistry and Molecular Biology, The University of Melbourne
- Assoc. Prof. Paul Baird, Centre for Eye Research Australia
- Professor Virginia Lee, University of Pennsylvania, Pennsylvania, USA
- Professor Malcolm Horne, The Howard Florey Institute
- Prof. Catriona McLean, Alfred Hospital, Vic.
- Dr. Genevieve Evin, Dr. Qiao-Xin Li, Dr. Anthony White, Assoc. Prof. Roberto Cappai from the Department of Pathology, University of Melbourne
- 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
Recent Publications
- 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. Accepted Mar 21, 09
- 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 accepted Feb 13, 09
- 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. 28, 2908-2919.
- Fodero-Tavoletti, M.T., Smith, D.P., McLean, C.A., Adlard, P.A., Barnham, K.J., Foster, L.E., Leone, L., Perez, K., Cortes, M., CULVENOR, J.G., Li,Q.X., Laughton, K.M., Rowe, C.C., Masters, C.L., Cappai, R., and Villemagne, V.L. (2007) In vitro characterization of Pittsburgh compound-B binding to Lewy bodies. J Neurosci. 27:10365-10371
- Li, Q.-X., Mok, S.S., Laughton, K.M., McLean, C.A., Cappai, R., Masters, C.L., CULVENOR, J.G., and Horne, M.K. (2007) Plasma a-synuclein is decreased in subjects with Parkinson’s disease. Exp. Neurol. 204, 583-577
- Melrose, H.L., Kent, C.B., Taylor, J.P., Dachsel, J.C., Hinkle, K.M., Lincoln, S.J., Mok, S.S., CULVENOR, J.G., Masters, C.L., Tyndall, G.M., Bass, D.I., Ahmed, Z., Andorfer, C.A., Ross, O.A., Wszolek, Z.K., DelleDonne, A., Dickson, D.W., and Farrer, M.J. (2007) A comparative analysis of Lrrk2 expression in mouse brain and Lewy Body disease. Neurosci. 147, 1047-1058
- Sim, C.H., Lio, D.S.S., Mok, S.S., Masters, C.L., Hill, A.F., CULVENOR, J.G., and H.-C. Cheng (2006) C-Terminal truncation and Parkinson’s disease-associated mutations down-regulate the protein serine/threonine activity of PTEN-induced Kinase-1 Hum. Mol. Genet., 15, 3251-3262
- Evin, G., Canterford, L.D., Hoke, D.E., Sharples, R.A., CULVENOR, J.G., and Masters, C.L. (2005) Transition-state analogue gamma-secretase inhibitors stabilize a 900 kDa prresenilin/nicastrin complex. Biochem. 44, 4332-4341.
- Cappai, R., Leck, S.L., Tew, D.J., Williamson, N.A., Smith, D.P., Galatis, D., Sharples, R.A., Curtain, C.C., Ali, F.E., Cherny, R.A., Culvenor, J.G., Bottomley S.P., Masters C.L., Barnham K.J., and Hill, A.F. (2005) Dopamine promotes a-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. FASEB J, 19,1377-1379.
- Hoke, D.E., Tan, J.L., Ilaya, N.T., CULVENOR, J.G., Smith, S., White, A.R., Masters, C.L., and Evin, G. (2005) In vitro g-secretase cleavage of the Alzheimer’s amyloid precursor protein correlates to a subset of presenilin complexes and is inhibited by zinc. FEBS J, 272,5544-5557
- Evin, G., Canterford, L.D., Hoke, D.E., Sharples, R.A., Culvenor, J.G., and Masters, C.L. (2005) Transition-state analogue gamma-secretase inhibitors stabilize a 900 kDa presenilin/nicastrin complex. Biochem . 44 , (4332-4341)
- Cappai R, Leck SL, Tew DJ, Williamson NA, Smith DP, Galatis D, Sharples RA, Curtain CC, Ali FE, Cherny RA, Culvenor JG , Bottomley SP, Masters CL, Barnham KJ, and Hill AF (2005) Dopamine promotes a-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. FASEB J, online June 9.
- Culvenor, J.G., Ilaya, N.T., Ryan, M.T., Canterford, L., Hoke, D., Williamson, N.A., McLean, C.A., Masters, C.L., and Evin, G. (2004) Characterization of Presenilin Complex from Mouse and Human Brain using Blue Native Gel Electrophoresis Reveals High Expression in Embryonic Brain and Minimal Change in Complex Mobility with Presenilin Mutations. Eur. J. Biochem. 271 , 375-385.
- Ilaya, NT., Evin, G., Masters, CL., and Culvenor, JG. (2004) Nicastrin expression in mouse peripheral tissues is not co-ordinated with Presenilin and is high in muscle . J. Neurochem. 91, 230-237.
- Smith, M. J., Sharples, R.A., Evin, G., McLean, C.A., Dean, B., Pavey, G., Fantino, E., Cotton, R.G.H., Imaizumi, K., Masters, C.L., Cappai, R., and Culvenor , J.G. (2004) Expression of truncated Presenilin 2 splice variant in Alzheimer's Disease, Bipolar Disorder, and Schizophrenia brain cortex . Molec. Brain Res. 127, 128-135.
- Gai, W.P., Pountney , D.L., Power, J.H.T., Li,Q.-X., Culvenor, J.G., McLean , C.A. , Jensen, P.H., and Blumbergs, P.C. (2003 ) a-Synuclein Fibrils Constitute the Central Core of Oligodendroglial Inclusion Filaments in Multiple System Atrophy. Exp. Neurol . 181 , 68-78.
- Sernee, M.F., Evin G., Culvenor J.G. , Villadangos, J.A., Beyreuther, K. Masters, C.L., and Cappai, R. (2003) Selecting cells with different Alzheimer's disease gamma-secretase activity using FACS. Differential effect on presenilin exon 9 gamma- and epsilon-cleavage. Eur. J. Biochem. 270 , 495-506.
- Beher, D., Fricker, M., Nadin, A., Clarke, E.E., Wrigley, J.D.J., Li, Y.-M., CULVENOR, J.G., Masters, C.L., Harrison , T., and Shearman, M.S. (2003) In Vitro Characterization of the Presenilin-dependent g-secretase Complex Using a Novel Affinity Ligand. Biochem. 42 , 8133-8142.
- Wickham , M.E. , Culvenor, J.G., and Cowman, A.F. (2003) Selective Inhibition of a Two-step Egress of Malaria Parasites from the Host Erythrocyte. J. Biol. Chem . 278 , 37658-37663.
- Culvenor, J.G., Rietze, R.L., Bartlett, P.F., Masters, C.L., and Li, Q.-X. (2002) Oligodendrocytes from Neural Stem Cells Express alpha-Synuclein: Increased Numbers from Presenilin 1 Deficient Mice. NeuroReport 13, 1305-1308.
- Mok, S.S., Turner, B.J., Beyreuther, K., Masters, C.L., Barrow, C.J., and Small, D.H. (2002) Toxicity of substrate bound amyloid peptides on vascular smooth muscle cells is enhanced by homocysteine. Eur. J. Biochem., 269, 3014-3022.
- Mok, S.S., Clippingdale, A.B., Beyreuther, K., Masters, C.L., Barrow, C.J. and Small D.H. (2000) Abeta peptides and calcium influence the secretion of the amyloid protein precursor from chick sympathetic neurons in culture. J. Neurosci Res. 15, 449-457.
- Culvenor, J.G., Evin, G., Cooney, M.A., Wardan, H., Robyn A. Sharples, Maher, F., Reed, G., Diehlmann, A., Weidemann, A., Beyreuther, K., and Masters, C.L. (2000) Presenilin 2 expression in neuronal cells: Induction during differentiation of embryonic carcinoma cells. Exp. Cell Res. 255, 192-206.
- Culvenor, J.G., McLean, C.A., Cutt, S., Campbell, B.C.V., Maher, F., Jäkälä, P., Hartmann, T., Beyreuther, K., Masters, C.M., and Qiao-Xin Li. (1999) Non-Abeta component of Alzheimer's disease amyloid (NAC) revisited: NAC and alpha-synuclein are not associated with Abeta amyloid. Am. J. Path. 155, 1173-1181
- Culvenor, J.G., Henry, A., Hartmann, T., Evin, G., Galatis, D., Friedhuber, A., Jayasena, U. L. H. R., Underwood, J.R., Beyreuther, K., Masters, C.L. and Cappai, R. (1998) Subcellular localization of the Alzheimer's disease amyloid precursor protein and derived peptides expressed in a recombinant yeast system. Amyloid Int. J. Exp. Clin. Invest. 5, 79-89.