|
|
|
|
|
| First Name: | Julian | | Last Name: | Thorpe | | Title: | Dr. | | Advanced Degrees: | D.Phil. | | Affiliation: | University of Sussex | | Department: | EM Division, The Sussex Centre for Advanced Microscopy | | Street Address 1: | School of Life Sciences | | Street Address 2: | Falmer | | City: | Brighton | | State/Province: | East Sussex | | Zip/Postal Code: | BN1 9QG | Country/Territory: | United Kingdom | | Phone: | +44 (0)1273 877585 | | Fax: | +44 (0)1273 678433 |
Disclosure:
(view policy)
|
Member reports no financial or other potential conflicts of interest. [Last Modified: 4 April 2012]
|
|
|
View all comments by Julian Thorpe
|
Tauopathies, Aging Process, Alzheimer Disease
|
Microscopy, Animal Models, Oxidative Stress, Apoptosis/Cell cycle, A-beta PP/A-beta, Neuropathology, Tau/Cytoskeleton
|
I am a biological electron microscopist by training. An interest in one particular protein, Pin1, has led me into the field of AD and the tauopathies. The development in this laboratory of a novel TEM labelling method utilising Pin1 (Thorpe et al., 1999) and the revelation of the involvement of Pin1 in AD (Lu et al., 1999) came fortuitously together at almost the same time. It would appear that Pin1 brings together many facets of AD, having an involvement in tangle formation , along with probable involvements in APP proteolysis (and thence plaque formation), the spurious up-regulation of cell cycle events , apoptosis and dysregulation of the Notch and Wnt pathways (via its interaction with beta-catenin).
|
Soura V, Stewart Parker M, Williams TL, Ratnayaka A, Atherton J, Gorringe K, Tuffin J, Darwent E, RambaranR, Klein W, Lacor P, Staras K, Thorpe J, Serpell L (2012) Visualisation of colocalisation in Ab42-administered neuroblastoma cells reveals lysosome damage and autophagosome accumulation related to cell death. Biochemical Journal 441:579-590
Page T, Gitcho MA, Mosaheb S, Carter D,Chakraverty S, Perry RH, Bigio EH, Gearing M, Ferrer I, Goate AM, Cairns NJ, Thorpe JR (2011) FUS immunogold labelling TEM analysis of the neuronal cytoplasmic inclusions of neuronal intermediate filament inclusion disease: a frontotemporal lobar degeneration with FUS proteinopathy. Journal of Molecular Neuroscience 45: 409-421 DOI: 10.1007/s12031-011-9549-8
Acevedo-Arozena A, Kalmar B, Essa S, Ricketts T, Joyce P, Kent R, Rowe C, Parker A, Gray A, Hafezparast M, Thorpe JR, Greensmith L, Fisher EMC (2011) A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis. Disease Models & Mechanisms 4: 686-700
Paine S, Bedford L, Thorpe JR, Mayer RJ, Bajaj N, Sheppard PW, Lowe J, Layfield R (2009) Immunoreactivity to Lys63-linked polyubiquitin is a feature of neurodegeneration. Neuroscience Letters 460: 205-208
Thorpe JR, Tang HHL, Atherton JM, Cairns NJ (2008) Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy. Journal of Neural Transmission 115: 1661-1671
Hashemzadeh-Bonehi L, Phillips RG, Cairns NJ, Mosaheb S, Thorpe JR (2006) Pin1 protein associates with neuronal lipofuscin: potential consequences in age-related neurodegeneration. Experimental Neurology 199: 328-338
MOSAHEB S, THORPE JR, HASHEMZADEH-BONEHI L, BIGIO EH, GEARING M, CAIRNS NJ (2005) Neuronal intranuclear inclusions are ultrastructurally and immunologically distinct from cytoplasmic inclusions of neuronal intermediate filament inclusion disease (NIFID). Acta Neuropathologica 110: 360-368
THORPE JR, MOSAHEB S, HASHEMZADEH-BONEHI L, CAIRNS NJ, KAY KE, MORLEY SJ, RULTEN S (2004) Shortfalls in the Peptidyl-Prolyl Cis-Trans Isomerase Protein Pin1 in Neurons are Associated With Frontotemporal Dementias. Neurobiology of Disease 17: 237-249
CAIRNS NJ, GROSSMAN M, ARNOLD SE, BURN DJ, JAROS E, PERRY RH, DUYCKAERTS C, STANKOFF B, PILLON B, SKULLERUD K, CRUZ-SANCHEZ FF, BIGIO EH, MACKENZIE IRA, GEARING M, JUNCOS JL, GLASS JD, YOKOO H, NAKAZATO Y, MOSAHEB S, THORPE JR, URYU K, LEE V.M.-Y, TROJANOWSKI, JQ (2004) Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease (NIFID). Neurology 63: 1376-1384
THORPE, J.R., MORLEY, S.J. and RULTEN, S.L. (2001) Utilising the Peptidyl- Prolyl Cis-Trans Isomerase Pin1 as a Probe of its Phosphorylated Target Proteins: Examples of Binding to Nuclear Proteins in a Human Kidney Cell Line and to Tau in Alzheimer’s Diseased Brain. J. Histochem. Cytochem. 49: 97-108
|
An overall comprehension of the process and progress of the disease that draws together its many facets and identifies the most likely points of effective therapeutic intervention. |
George R. Jackson, Martina Wiedau-Pazos, Tzu-Kang Sang, Naveed Wagle, Carlos A. Brown, Sasan Massachi and Daniel H. Geschwind (2002) Human Wild-Type Tau Interacts with wingless Pathway Components and Produces Neurofibrillary Pathology in Drosophila Neuron 34: 509-519
Mudher A, Lovestone S (2002)Alzheimer’s disease – do tauists and baptists finally shake hands? Trends in Neurosciences 25: 22-26
Lee, VMY, Goedert, M and Trojanowski, JQ (2001)
Neurodegenerative tauopathies. ANNUAL REVIEW OF NEUROSCIENCE 24: 1121-1159
|
I would continue my research on Pin1 protein as it appears to bring together many facets of AD, having an involvement in tangle formation, along with probable involvements in APP proteolysis (and thence plaque formation), the spurious up-regulation of cell cycle events, apoptosis and dysregulation of the Notch and Wnt pathways (via its interaction with beta-catenin).
|
That nuclear Pin1 depletion - in the presence of associated upregulation of cell cycle events - in AD leads to nuclear instability and apoptosis, and that this depletion might well be a unifying, contributory factor towards neuronal cell death in AD and potentially all the tauopathies. |
Correlating the timing of nuclear depletion of Pin1 and increased amounts, and the identification, of phosphorylated nuclear Pin1 targets with the appearance of apoptotic markers would be a starting point. |
|
|
|
|
|
|
Home
