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Department of Physiology, Development and Neuroscience

 

Research

Intracellular protein misfolding and aggregation are features of many late-onset neurodegenerative diseases (ND), called proteinopathies. These include Alzheimer’s disease, Parkinson’s disease, tauopathies and Huntington’s Disease. Currently, there are no effective strategies that slow or prevent the neurodegeneration resulting from these diseases in humans. These diseases are predicted to cause increasing economic and social burdens on society particularly as lifespan increases, hence the need for a better understanding of their biology and identification of therapeutic targets. Our work focuses on the roles of intracellular aggregate-prone proteins in the pathogenesis of ND and seeks to identify pathways which can enhance the clearance of these toxic proteins. We use zebrafish models of neurodegeneration to determine how different genetic modifiers affect disease severity and to identify novel therapeutic compounds which may be used as potential treatments for such diseases. 

Collaborators

Professor David Rubinsztein – Cambridge Institute for Medical Research

Publications

Key publications: 

Lopez A, Lee SE, Wojta K, Ramos EM, Klein E, Chen J, Boxer AL, Gorno-Tempini ML, Geschwind DH, Schlotawa L, Ogryzko NV, Bigio EH, Rogalski E, Weintraub S, Mesulam MM; Tauopathy Genetics Consortium, Fleming A, Coppola G, Miller BL, Rubinsztein DC. (2017) A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction. Brain, 140(4):1128-1146

Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, Füllgrabe J, Jackson A, Jimenez Sanchez M, Karabiyik C, Licitra F, Lopez Ramirez A, Pavel M, Puri C, Renna M, Ricketts T, Schlotawa L, Vicinanza M, Won H, Zhu Y, Skidmore J, Rubinsztein DC. (2017), Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. Neuron, 2017 Mar 8;93(5):1015-1034.

Menzies FM, Fleming A, Rubinsztein DC, (2015), Compromised autophagy and neurodegenerative diseasesNat Rev Neurosci, 16(6):345-57

Jimenez-Sanchez M, Lam W, Hannus M, Sönnichsen B, Imarisio S, Fleming A, Tarditi A, Menzies F, Ed Dami T, Xu C, Gonzalez-Couto E, Lazzeroni G, Heitz F, Diamanti D, Massai L, Satagopam VP, Marconi G, Caramelli C, Nencini A, Andreini M, Sardone GL, Caradonna NP, Porcari V, Scali C, Schneider R, Pollio G, O'Kane CJ, Caricasole A, Rubinsztein DC, (2015), siRNA screen identifies QPCT as a druggable target for Huntington's diseaseNat Chem Biol, 11(5):347-54

Moreau K, Fleming A, Imarisio S, Lopez Ramirez A, Mercer JL, Jimenez-Sanchez M, Bento CF, Puri C, Zavodszky E, Siddiqi F, Lavau CP, Betton M, O'Kane CJ, Wechsler DS, Rubinsztein DC, (2014), PICALM modulates autophagy activity and tau accumulationNat Commun, 22;5:4998

Fleming A, Diekmann H, Goldsmith P, (2013), Functional characterisation of the maturation of the blood-brain barrier in larval zebrafishPLoS One, 8(10):e77548 

Renna M, Bento CF, Fleming A, Menzies FM, Siddiqi FH, Ravikumar B, Puri C, Garcia-Arencibia M, Sadiq O, Corrochano S, Carter S, Brown SD, Acevedo-Arozena A, Rubinsztein DC, (2013), IGF-1 receptor antagonism inhibits autophagy, Hum Mol Genet, 22(22):4528-44

Fleming A, Alderton WK, (2012), Zebrafish in pharmaceutical industry research: finding the best fitDrug Discovery Today: Disease Models, 10(1):e43-50

Fleming A, Noda T, Yoshimori T, Rubinsztein DC, (2011), Chemical modulators of autophagy as biological probes and potential therapeutics, Nat Chem Biol, 7(1):9-17

Fleming A, Rubinsztein DC, (2011), Zebrafish as a model to understand autophagy and its role in neurological disease, Biochim Biophys Acta, 1812(4):520-526

Lichtenberg M, Mansilla A, Zecchini V, Fleming A, Rubinsztein DC, (2011), The Parkinson’s Disease protein LRRK2 impairs proteasome substrate clearance without affecting proteasome catalytic activity, Cell Death Dis, 2:e196

Group Leader
 Angeleen  Fleming

Contact Details

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