Professor Stephen B Wharton
Professor and Honorary consultant in Neuropathology
Department of Neuroscience
Sheffield Institute of Translational Neuroscience
University of Sheffield
385a Glossop Road
Secretary: Bev Carter
Tel: +44 (0)114 22 22295
2014 - present: Professor in Neuropathology, Sheffield University
Professor Wharton’s research interest are focused on the cellular and molecular pathology of dementia and brain ageing. His major areas of interest are in:
Current funding sources
Defective nutrient signalling and dementia: an epidemiological neuropathology approach. Funded by the Alzheimer’s Society, this project examines the effects of diabetes on the brain. Diabetes is a major risk factor for dementia and Alzheimer’s disease, but the mechanisms by which it contributes to cognitive decline are unclear. We seek to define the contribution of diabetes and related metabolic changes to dementia, and to identify novel mechanisms by which it damages different key cell types within the brain; the nerve cells, the cells that line brain blood vessels and the astrocyte, which supports and integrates the functions of the other two types. Using autopsy-brain samples from the Cognitive Function and Ageing Study (CFAS), we plan to investigate the relationship of diabetes to dementia and to Alzheimer’s pathology and vascular pathology. The CFAS brain-donation cohort, held in Sheffield, is from a population (rather than clinic) based sample of over 65yr olds; its unselected nature means that it is ideal for examining interactions between pathologies and relationships to dementia in an unbiased way. Cells in the brain and elsewhere are able to sense changes to nutrients, such as glucose, with specialised signalling pathways. Alterations in these pathways may impair the ability of nerve cells to function, so we are examining the impact of diabetes on them. We use methods that allow us to examine overall changes in the activities of genes in cells to identify new mechanisms by which diabetes impairs different brain cell-types. Obesity and diabetes are increasing problems. This proposal will better define how they contribute to dementia.
A Cellular Pathology and Gene Expression Approach to Understand the Basis of Progressive Dementia Occurring After Stroke. This work is funded by the Alzheimer’s Society and is a collaboration with Prof Kalaria at the University of Newcastle. Around a quarter of stroke survivors develop progressive dementia after more than 3-6 months, and with more stroke survivors, post stroke dementia is an increasing problem. We aim to identify cell mechanisms that can cause post-stroke dementia. We are using brain tissue donated to the Cognitive Function After Stroke Study (CogFAST), which includes individuals with and without dementia after stroke. Previous work showed that the front of the brain is particularly affected, with leakiness of small blood vessels in the white matter. This can damage the processes or wires of nerve cells that pass through this area. We are isolating different cell types in this area and using methods to examine changes in the patterns of gene expression in these cells. This has the potential to identify new mechanisms that contribute to a stroke survivor developing dementia, and which might lead to new treatments.
Cholesterol Dysregulation in the Neurovascular Unit as an Early Contributor to Neuronal Dysfunction in Alzheimer’s Disease. This is a PhD studentship funded by Alzheimer’s Research UK.
Variation in Astrocyte Responses to Different Molecular Pathologies and the Effect on Neuroprotection. This is a PhD studentship funded by the Alzheimer’s Society.
The Effects of Systemic Atherosclerosis on the Brain Neurovascular Unit. A collaboration with Prof Sheila Francis in Cardiovascular Sciences, this PhD studentship is funded by Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico
Additional Collaborations. Work on the role of neuroinflammation in dementia, with Dr Julie Simpson, and on Gene Based Therapies for Frontotemporal dementia (ARUK-funded) with Prof Mimoun Azzouz.
Current PhD students:
External professional activities – current and recent
Membership of associations and societies - current
|Publications||Ameen-Ali KE, Simpson JE, Wharton SB, Heath PR, Sharp P, Brezzo G, Berwick J. The time course of recognition memory impairment and glial pathology in the hAPP-J20 mouse model of Alzheimer’s disease. J Alzheimers Dis in press doi: 10.3233/JAD-181238
Wharton SB, Verber NS, Wagner BE, Highley JR, Fillingham DJ, Waller R, Strand K, Ince PG, Shaw PJ. Combined FUS+ Basophilic inclusion body disease and atypical tauopathy presenting with an ALS/MND-plus phenotype. Neuropathol Appl Neurobiol 2019; in press doi: 10/1111/nan12542.
Waller R, Murphy M, Garwood CJ, Jennings L, Heath PR, Chambers A, Matthews FE, Brayne C, Ince PG, Wharton SB, Simpson JE. Metallothionein-I/II expression associates with the astrocyte DNA damage response and not Alzheimer-type pathology in the ageing brain. Glia 2018; 66:2316-2323.
Ratcliffe LE, Vazquez-Villasenor I, Jennings L, Heath PR, Mortiboys H, Schwartzentruber A, Karyka E, Simpson JE, Ince PG, Garwood CJ, Wharton SB. Loss of IGF1R in human astrocytes alters complex I activity and support for neurons. Neuroscience 2018; 390:46-59.
Morgan SV Garwood CJ, Jennings L, Simpson JE, Castelli LM, Heath PR, Mihaylov SR, Vazquez Villasenor I, Ince PG, Dickman M, Hautbergue GM, Wharton SB. Proteomic and cellular localisation studies suggest non-tight junction cytoplasmic and nuclear roles for occludin in astrocytes. Eur J Neurosci 2018; 47:1444-1456.
Kingston A, Wohland P, Wittenberg R, Robinson L, Brayne C, Matthews FE, Jagger CE, Cognitive Function and Ageing Studies (CFAS). Is late-life dependency increasing or not? A comparison of the cognitive function and ageing studies (CFAS). Lancet 2017; 390:1676-1684. (Listed as a member of the CFAS Collaboration).
Kovacs GG, Xie SX, Lee EB, Robinson JL, Caswell C, Irwin DJ, Toledo JB, Johnson VE, Smith DH, Alafuzoff I, Attems J, Bencze J, Bieniek KF, Bigio EH, Bodi I, Budka H, Dickson DW, Dugger BN, Duyckaerts C, Ferrer I, Forrest SL, Gelpi E, Gentleman SM, Giaccone G, Grinberg LT, Halliday GM, Hatanpaa KJ, Hof PR, Hofer M, Hortobágyi T, Ironside JW, King A, Kofler J, Kövari E, Kril JJ, Love S, Mackenzie IR, Mao Q, Matej R, McLean C, Munoz DG, Murray ME, Neltner J, Nelson PT, Ritchie D, Rodriguez RD, Rohan Z, Rozemuller A, Sakai K, Schultz C, Seilhean D, Smith V, Tacik P, Takahashi H, Takao M, Rudolf Thal D, Weis S, Wharton SB, White CL 3rd, Woulfe JM, Yamada M, Trojanowski JQ. Multisite assessment of ageing-related tau astrogliopathy (ARTAG). J Neuropathol Exp Neurol 2017; 76:605-619.
Schwalbe EC, Lindsey JC, Nakjang S, Crosier S, Smith AJ, Hicks D, Rafiee G, Hill RM, Iliasova A, Stone T, Pizer B, Michalski A, Joshi A, Wharton SB, Jacques TS, Bailey S, Williamson D, Clifford SC. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncol 2017; 18:958-971.
Goodall EF, Wang C, Simpson JE, Baker DJ, Drew DR, Heath PR, Saffrey MJ, Romero IA, Wharton SB. Age-associated changes in the blood brain barrier: Comparative studies in human and mouse. Neuropathol Appl Neurobiol 2018; 44:328-340.
Waller R, Woodroofe MN, Wharton SB, Ince PG, Francese S, Heath PR, Cudzich-Madry A, Thomas RH, Rounding N, Sharrack B, Simpson JE. Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role. J Neuroimmunol 2016; 299:139-146.
Ince PG, Minett T, Forster G, Brayne C, Wharton SB. Microinfarcts in an older population-representative brain donor cohort (MRC-CFAS): Prevalence, relation to dementia and mobility, and implications for the evaluation of cerebral Small Vessel Disease. Neuropathol Appl Neurobiol 2017; 43:409-418.
Appleby-Mallinder C, Wyles MD, Simpson JE, Wharton SB, Ince PG, Heath PR. Expression microdissection of enriched cell populations from archival brain tissue. J Neurosci Methods 2016: 268:125-130.
* Matthews FE, Stephan BCM, Robinson L, Jagger C, Barnes LE, Arthur A, Brayne C, Cognitive Function and Ageing Studies (CFAS) Collaboration*. A two decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II. Nat Commun 2016; 7:11398. [*Listed as a member of the Collaboration].
Wharton SB, Minett T, Drew DR, Forster G, Matthews F, Brayne C, Ince PG. Epidemiological pathology of tau in the ageing brain. Application of staging for neuropil threads (BrainNet Europe Protocol) to the MRC Cognitive Function and Ageing Brain Study. Acta Neuropathol Commun 2016; 4:11.
Kovacs GG, Ferrer I, Grinberg LT, Alafuzoff I, Attems J, Budka H, Cairns NJ, Crary JF, Duyckaerts C, Ghetti B, Halliday GM, Ironside JW, Love S, Mackenzie IR, Munoz DG, Murray ME, Nelson PT, Takahashi H, Trojanowski JQ, Ansorge O, Arzberger T, Baborie A, Beach TG, Bieniek KF, Bigio EH, Bodi I, Dugger BN, Feany M, Gelpi E, Gentleman SM, Giaccone G, Hatanpaa KJ, Heale R, Hof PR, Hofer M, Hortobagyi T, Jellinger K, Jicha GA, Ince P, Kofler J, Kovari E, Kril JJ, Mann DM, Matej R, McKee AC, McLean C, Milenkovic I, Montine TJ, Murayama S, Lee EB, Rahmini J, Rodriguez RD, Rozemuller A, Schneider JA, Schultz C, Seeley, Seilhean D, Smith C, Tagliavini F, Takao M, Thal DR, Toledo JB, Tolnay M, Troncoso JC, Vinters HV, Weis S, Wharton SB, White CL, Wisniewski T, Woulfe JM, Yamada M, Dickson DW. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol 2016; 131:87-102.
Bargiela D, Shangmugarajah S, Lo C, Blakely EL, Taylor RW, Horvath R, Wharton S, Chinnery PF, Hadjivassiliou M. Mitochondrial pathology in progressive cerebellar ataxia. Cerebellum Ataxias 2015; 2:16
Fluteau A, Ince PG, Minett T, Matthews FE, Brayne C, Garwood CJ, Ratcliffe LE, Morgan S, Heath PR, Shaw PJ, Wharton SB, Simpson JE; MRC Cognitive Function Ageing Neuropathology Study Group. The nuclear retention of transcription factor FOXO3a correlates with a DNA damage response and increased glutamine synthetase expression by astrocytes suggesting a neuroprotective role in the ageing brain. Neurosci Lett 2015; 609:11-17.
Garwood CJ, Ratcliffe LE, Morgan SV, Simpson JE, Owens H, Vazquez-Villasenor I, Heath PR, Romero IA, Ince PG, Wharton SB. Insulin and IGF-1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors. Mol Brain 8:51 DOI 10.1186/s13041-015-0138-6. [Listed as one of the most influential articles in the journal in 2016 according to Altmetric.com].
Stratmann K, Heinsen H, Korf HW, Del Turco D, Ghebremedhin E, Seidel K, Bouzrou M, Grinberg LT, Bohl, J, Wharton SB, den Dunnen W, Rub U. Precortical phase of Alzheimer’s disease (AD)-related tau cytoskeletal pathology. Brain Pathol 2016; 26:371-386.
Highley JR, Lorente Pons A, Cooper-Knock J, Wharton SB, Ince PG, Shaw PJ, Wood J, Kirby J. Motor neurone disease/amyotrophic lateral sclerosis associated with intermediate-length CAG repeat expansions in Ataxin-2 does not have 1C2-positive polyglutamine inclusions. Neuropathol Appl Neurobiol In Press
Simpson JE, Ince PG, Minett T, Matthews FE, Heath PR, Shaw PJ, Goodall E, Garwood CJ, Ratcliffe LE, Brayne C, Rattray M, Wharton SB, on behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group. Neuronal DNA damage response-associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of Alzheimer-type pathology. Neuropathol Appl Neurobiol 2016; 42:167-179.
Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, Pickering-Brown S, Kirby J, Hautbergue GM, Shaw Pj. Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43-proteinopathy. Acta Neuropathol 2015; 130:63-75.
Mathur R, Ince PG, Minett T, Garwood CJ, Shaw PJ, Matthews FE, Brayne C, Simpson JE, Wharton SB. A reduced astrocyte response to -amyloid plaques in the ageing brain associates with cognitive impairment. PLoS ONE 2015 10(2): e0118463. Doi:10.1371/journal.pone.0118463.
Hill RM, Kuijper S, Lindsey JC, Petrie K, Schwalbe EC, Barker K, Boult JK, Williamson D, Ahmad Z, Hallsworth A, Ryan SL, Poon E, Robinson SP, Ruddle R, Raynaud FI, Howell L, Kwok C, Joshi A, Nicholson SL, Crosier S, Ellison DW, Wharton SB, Robson K, Michalski A, Hargrave D, Jacques TS, Pizer B, Bailey S, Swartling FJ, Weiss WA, Chesler L, Clifford SC. Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive therapeutically targetable disease. Cancer Cell 2015; 27:72-84.
Simpson JE, Ince PG, Matthews FE, Shaw PJ, Heath PR, Brayne C, Garwood C, Higginbottom A, Wharton SB, on behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group. A neuronal DNA damage response is detected at the earliest stages of Alzheimer’s neuropathology and correlates with cognitive impairment in the MRC-CFAS ageing brain cohort. Neuropathol Appl Neurobiol 2015; 41:483-496.
Beer AM, Cooper-Knock J, Higginbottom A, Highley JR, Wharton SB, Ince PG, Milano A, Jones AA, Al-Chalabi A, Kirby J, Shaw PJ. Intermediate length C9orf72 expansion in an ALS patient without classical C9orf72 neuropathology. Amyotroph Lateral Scler Frontotemporal Degener 2015; 16:249-251.
Al-Mashhadi S, Simpson JE, Heath PR, Dickman M, Forster G, Matthews FE, Brayne C, Ince PG,Wharton SB; Medical Research Council Cognitive Function and Ageing Study. Oxidative glial cell damage associated with white matter lesions in the aging human brain. Brain Pathol 2015; 25:565-574.
Alafuzoff I, Pikkarainen, M, Neumann M, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Bugiani O, Ferrer I, Gelpi E, Gentleman S, Giaccone G, Graeber MB, Hortobagyi T, Ince PG, Ironside JW, Kavantas N, King A, Korkolopoulou P, Kovacs GG, Meyronet D, Monoranu C, Nilsson T, Parchi P, Patsouris E, Revesz T, Roggendorf W, Rozemuller A, Seilhean D, Streichenberger N, Thal DR, Wharton SB, Kretzschmar, H. Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP-43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium. J Neural Transm 2015; 122:957-72.
Cooper-Knock J, Walsh MJ, Higginbottom A, Highley JR, Dickman MJ, Edbauer D, Ince PG, Wharton SB, Wilson SA, Kirby J, Hautbergue GM, Shaw PJ. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 2014; 137:2040-2051.
Garwood CJ, Simpson JE, Al Mashhadi S, Axe C, Wilson S, Heath PR, Shaw PJ, Matthews FE, Brayne C, Ince PG, Wharton SB, MRC Cogntive Function and Ageing Study. DNA damage response and senescence in endothelial cells of human cerebral cortex and relation to Alzheimer’s neuropathology progression: a population-based study in the MRC-CFAS cohort. Neuropathol Appl Neurobiol 2014; 40:802-814.
Highley JR, Kirby J, Jansweijer JA, Webb PS, Hewamadduma CA, Heath PR, Higginbottom A, Raman R, Ferraiuolo L, Cooper-Knock J, McDermott CJ, Wharton SB, Shaw PJ, Ince PG. Loss of nuclear TDP-43 in ALS causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurons. Neuropathol Appl Neurobiol 2014; 40:670-685.
Asi YT, Simpson JE, Heath PR, Wharton SB, Lees AJ, Revesz T, Houlden H, Holton JL. Alpha-synuclein expression in oligodendrocytes in MSA. Glia 2014; 62:964-970.
Janaway BM, Simpson JE, Hoggard N, Highley JR, Forster G, Drew D, Gebril OH, Matthews FE, Brayne C, Wharton SB, Ince PG. Brain haemosiderin in older people: pathological evidence for an ischaemic origin of MRI microbleeds. Neuropathol Appl Neurobiol 2014; 40:258-269.
Gallagher MD, Suh E, Grossman M, Elman, L, McCluskey L, Van Swieten JC, Al‑Sarraj S, Neumann M, Gelpi E, Ghetti B, Rohrer JD, Halliday G, Van Broeckhoven C, Seilhean D, Shaw PJ, Frosch MP, Alafuzoff I, Antonell A, Bogdanovic N, Brooks W, Cairns NJ, Cooper-Knock J, Cotman C, Cras P, Cruts M, De Deyn PP, DeCarli C, Dobson-Stone C, Engelborghs S, Fox N, Galasko D, Gearing M, Gijselinck I, Grafman J, Hartikainen P, Hatanpaa KJ, Highley JR, Hodges J, Hulette C, Ince PG, Jin LW, Kirby J, Kofler J, Kril J, Kwok JBJ, Levey A, Lieberman A, Llado A, Martin JJ, Masliah E, McDermott CJ, McKee A, McLean C, Mead S, Miller CA, Miller J, Munoz DG, Murrell J, Paulson H, Piguet O, Rossor M, Sanchez-Valle R, Sano M, Schneider J, Silbert LC, Spina S, van der Zee J, Van Langenhove T, Warren, J, Wharton SB, White CL, Woltjer RL, Trojanowski JQ, Lee VMY, Van Deerlin, V, Chen-Plotkin A. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol 2014; 127:407-418.