Steven Collins
| Contact: | Steven Collins |
|---|---|
| Phone: | +61 3 8344 1949 |
| Fax: | +61 3 834 9 5105 |
| Email: | stevenjc@unimelb.edu.au |
The transmissible spongiform encephalopathies (TSEs) are a biologically unique group of neurodegenerative diseases that afflict both humans (e.g. Creutzfeldt-Jakob disease, kuru, fatal familial insomnia) and animals (e.g. scrapie, bovine spongiform encephalopathy [“mad cow disease”]). One very important differentiating feature compared to other neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, is the transmissibility of TSEs. Current understanding supports the hypothesis that the infectious unit is composed primarily (or perhaps solely) of abnormal, protease-resistant conformations (PrPres) of the normal host encoded prion protein (PrPc), and research has indicated that transmissibility and pathogenesis are not necessarily linked. Many important aspects of prion biology remain to be answered including: the normal function of PrPc; the primary pathogenic mechanisms of disease; the structure of PrPres; the precise cellular location and mechanisms of conversion.
Key research areas:
Epidemiological:
- National surveillance of all human forms of transmissible spongiform encephalopathies (TSEs) to allow various analyses including: temporal trends, identification of risk factors for disease occurrence, recognition of case clustering, delineation of phenotypic subtypes and cognate differences in utility of diagnostic investigations, and detection of new prion protein gene mutations.
Neuroscience:
A broad range of techniques are currently being used to study the following areas of prion disease.
- examining normal membrane processing and trafficking of PrPc. Concomitantly we are examining those cellular properties essential to the conversion of PrPc to PrPres and the subsequent cellular persistence of PrPres.
- assessing whether PrPc to PrPres conversion is directly linked to pathogenic cellular events such as lipid peroxidation.
- assessing whether proteasomal dysfunction is a primary pathogenic mechanism of prion disease.
- assessing the role of redox active transition metals (such as copper and manganese) in PrPc to PrPres conversion as well as their role in determining secondary structure.
Objectives:
- Determine risk factors for human TSEs.
- Develop diagnostic investigations.
- Develop therapies for prion disease.
- Determine cellular mechanisms that facilitate PrPc to PrPres conversion and promote persistent PrPres propagation.
- Determine primary pathogenic mechanisms of prion disease.
Major Achievements:
- Determined national incidence and phenotypes of all forms of human TSEs.
- Clarified the molecular-clinical profiles of Australian sporadic CJD and their likely endogenous determination.
- Identified repeated surgical procedures as a risk factor for “sporadic” CJD.
- Delineated and validated the diagnostic utility of CSF 14-3-3 protein testing for sporadic CJD.
- Reported three novel prion protein gene mutations as causes of CJD.
- Determined the inefficacy of quinacrine as a treatment for human prion disease based on in vivo studies.
- Determined the high frequency of protracted asymptomatic prion disease after low dose inoculation and the implications for infection control.
Techniques:
- National surveillance data base of all human TSEs for epidemiological analysis.
- In vivo and in vitro models of prion disease.
- Cell free conversion systems.
Collaborations:
Departmental:
Drs Victoria Lawson, Kevin Barnham, Anthony White, Robert Cherny, Cyril Curtain, Roberto Cappai, Damian Holsinger.
The University of Melbourne:
Dr Andrew Hill (Biochemistry).
External:
Dr Simon Hawke, the University of Sydney.
International:
The EUROCJD surveillance consortium; Professor Markus Glatzel, Hamburg, Germany.
Funding:
The Australian National Creutzfeldt-Jakob Disease Registry is funded by the Commonwealth Department of Health and Ageing. Research is also funded through an NHMRC Program Grant.
Selected Recent Publications:
- S Collins,M Law, A Fletcher, A Boyd, J Kaldor, CL Masters. Surgical treatment and risk of sporadic Creutzfeldt-Jakob disease: a case control study. Lancet 1999; 353: 693-697.
- A White, S Collins, L. Stewart, J Thyer, F Maher, C Masters, R Cappai. Prion protein deficient neurons reveal lower glutathione reductase activity and increased susceptibility to hydrogen peroxide toxicity. American Journal of Pathology 1999; 155: 1723-1730.
- S Collins, A Boyd, A Fletcher, K Byron, C Harper, C McLean, CL Masters. Novel prion protein gene mutation in an octogenerian with Creutzfeldt-Jakob disease. Archives of Neurology 2000; 57: 1058-1063.
- S Collins, A Boyd, A Fletcher, M Gonzales, C McLean, C Masters. Recent advances in the pre-mortem diagnosis of Creutzfeldt-Jakob disease. Journal of Clinical Neuroscience 2000; 7: 195-202.
- S Collins, A Boyd, A Fletcher, M Gonzales, C McLean, K Byron, C Masters. Creutzdeldt-Jakob disease: diagnostic utility of 14-3-3 protein immunodetection in cerebrospinal fluid. Journal of Clinical Neuroscience 2000; 7: 203-208.
- I Zerr, M Pocchiari, S Collins, JP Brandel, J De Pedro Cuesta, RSG Knight, H Bernheimer, F Cardone, N Delasnerie-Laupretre, N Cuadrado Corrales, A Ladogana, M Bodemer, A Fletcher, T Awan, A Ruiz Bremon, H Budka, JL Laplanche, RG Will and S Poser. Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease. Neurology 2000; 55: 811-815.
- P Brown, M Preece, J-P Brandel, T Sato, L. McShane, I Zerr, A Fletcher, RG Will, M Pocchiari, N Cashman, JH d’Aignaux, L Cervenáková, J Fradkin, L Schonberger,SJ Collins. Iatrogenic Creutzfeldt-Jakob disease at the Millenium. Neurology 2000; 55: 1075-1081.
- Collins S, Boyd A, Fletcher A, Hill A, Farish S, J Kaldor, Z Ansari, Smith M, Masters CL. Creutzfeldt-Jakob disease cluster in an Australian rural city.Annals of Neurology 2002; 52: 115-118.
- Collins S, Boyd A, Fletcher A, V Lewis, Lee JS, Law M, Kaldor, J Masters CL. Creutzfeldt-Jakob disease in Australia, 1970 to 1999. Neurology 2002; 59: 1365-1371.
- Collins S , Lewis V, Brazier M, Hill A, Fletcher A, Masters CL. Quinacrine does not prolong survival in a murine Creutzfeldt-Jakob disease model. Annals of Neurology 2002; 52: 503-506.
- Lewis V, Boyd A, Masters CL, Collins SJ. Apparently sporadic CJD and covert health care transmissions. The Lancet Neurology 2002; 1: 470-471.
- Lewis V, Collins S, Hill AF, Boyd A, McLean CA, Smith M, Masters CL. Novel prion protein insert mutation associated with prolonged neurodegenerative illness. Neurology 2003; 60: 1620-1624.
- Collins S, Lawson V, Masters CL. Transmissible spongiform encephalopathies. Lancet 2004; 363: 51-61.
- Brooke FJ, Boyd A, Klug G, Masters CL and Collins SJ. Lyodura use and the risk of iatrogenic Creutzfeldt-Jakob disease in Australia. Medical Journal of Australia 2004; 180: 177-181.
- Holsinger RMD, McLean CA, Collins SJ, Masters CL, Evin G. Increased β-secretase activity in cerebrospinal fluid of Alzheimer’s disease subjects. Annals of Neurology 2004; 55: 898-899.
- Pocchiari M, Puopolo M, Croes E, Budka H, Gelpi E, Collins S, Lewis V, et al. Determinants of survival in sporadic Creuzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Brain 2004; 127: 2348-2359.
- Collins S, Brazier M, Lewis V, Hill AF, Lawson V, Klug G, Masters CL. Extended period of asymptomatic prion disease after low dose inoculation: assessment of detection methods and implications for infection control. In press – Neurobiology of Disease.
- Ladogna A, Puopolo M, Croes EA, Budka H, Jarius C, Collins S, Klug GM, et al. Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia and Canada. Neurology 2005; 64: 1586-1591.
- Lewis V, Hill AF, Klug GM, Boyd A, Masters CL, Collins SJ. Australian sporadic CJD analysis supports endogenous determinants of molecular-clinical profiles. Neurology 2005; 65: 113-118.
- Lawson VA , Collins SJ, Masters CL, Hill AF. Prion protein glycosylation. Journal of Neurochemistry 2005; 93: 793-801.
- Kovács GG, Puopolo M, Ladogana A, Pocchiari M, Budka H, van Duijn C, Collins SJ, Boyd A, Giulivi A, Delasnerie-Laupretre N, Brandel J-P, Zerr I, Kretschmar HA, Pedro de Cuesta J, Calero-Lara M, Glatzel M, Aguzzi A, Bishop M, Knight R, Belay G, Will RG, Mitrova E. Genetic prion disease: the EUROCJD experience. Human Genetics 2005; 118: 166-174.
- Brazier MW, Lewis V, Ciccotosto GD, White AR, Hill AF, Cappai R, Ironside J, Lawson VA, Klug GM, Masters CL, Collins SJ. Correlative studies support lipid peroxidation is linked to PrPres propagation as an early primary pathogenic event in prion disease. Brain Research Bulletin 2006; 68: 346-354.
- Collins SJ, Sanchez-Juan P, Masters CL, Klug GM, van Duijn C, Poleggi A, Pocchiari M, Almonti S, Cuadrado-Corrales N, de Pedro-Cuesta J, Budka H, Gelpi E, Glatzel M, Tolnay M, Hewer E, Zerr I, Heinemann U, Kretszchmar HA, Jansen GH, Olsen E, Mitrova E, Alpérovitch A, Brandel J-P, Mackenzie J, Murray K, Will RG. Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease. Brain 2006; 129: 2278-2287.
- Holsinger RMD, Lee JS, Boyd A, Masters CL, Collins SJ. CSF BACE1 activity is increased in CJD and Alzheimer’s disease compared to other dementias. Neurology 2006; 67: 710-712.
- 2006.5 de Pedro-Cuesta J, Glatzel M, Almazan J, Stoeck K, Mellina V, Puopolo M, Pocchiari M, Zerr I, Kretzschmar H, Brandel J-P, Delasnerie-Laupretre N, Alperovitch A, van Duijn C, Sanchez-Juan P, Collins S, Lewis V, Jansen GH, Coulthart MB, Gelpi E, Budka H, Mitrova E. Human transmissible spongiform encephalopathies in eleven countries: diagnostic pattern across time, 1993-2002. BMC Public Health 2006; 6: 278.
- Rowe DB, Lewis V, Needham M, Rodriguez M, Boyd A, McLean C, Roberts H, Masters CL, Collins SJ. Novel prion protein gene mutation presenting with subacute PSP-like syndrome. Neurology 2007; 68: 868-870.
- Brazier MW, Doctrow SR, Masters CL, Collins SJ. A manganese-superoxide dismutase/catalase mimetic extends survival in a mouse model of human prion disease. Free Radical Biology and Medicine 2008; 45: 184-192.
- Lawson VA, Vella L, Stewart J, Sharples R, Klemm H, Machalek DM, Masters CL, Cappai R, Collins SJ, Hill AF. Mouse-adapted sporadic human CJD prions propagate in cell culture. International Journal of Biochemistry and Cell Biology 2008; 40: 2793-2801.
- Klug GMA, Wand H, Boyd A, Law M, Kaldor J, Masters CL, Collins SJ. Enhanced geographically-restricted surveillance simulates sporadic Creutzfeldt-Jakob disease clustering. Brain 2009; 132: 493-501.
- 2009.1 Brazier MW, Wall VA, Brazier BW, Masters CL, Collins SJ. Therapeutic interventions ameliorating prion disease. Expert Reviews Anti-Infective Therapy 2009; 7: 83-105.