Biography
Angeleen Fleming obtained her degree from UCL and PhD from Great Ormond Street Institute of Child Health and has worked in both academia and biotech. She has ~20 years’ experience of working with zebrafish as a model organism and has run a zebrafish research group at the University of Cambridge since 2009. Work in the Fleming lab has two main focuses: firstly, developing and using zebrafish transgenic models of neurodegenerative disease to understand the causes of neurodegeneration and to investigate therapeutic mechanisms and secondly, to elucidate the role of autophagy and other protein clearance pathways in vivo in normal physiology and in pathological conditions.
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.
To date, we have has developed and characterised 11 different zebrafish transgenic models of neurodegenerative disease to understand the causes of neurodegeneration and to investigate therapeutic mechanisms. In addition, we have developed zebrafish fluorescent reporter lines to elucidate the role of autophagy and other protein clearance pathways in normal physiology and in pathological conditions. Using the photoconvertible protein Dendra2 fused to disease-causing, aggregate-prone proteins, we have developed a method to measure the clearance of such proteins from neurons in vivo (Lopez et al., 2017; Siddiqi et al., 2019; VerPlank et al., 2020; Lopez et al., 2022). Recently, we have also developed a suite of transgenic lines that allow us to spatially and temporally control autophagic flux (Schlotawa et al., 2023). Using these tools, we can investigate how cell- or tissue-specific changes in autophagic flux affects processes such as aging, inflammation and neurodegeneration in vivo.
Professor David Rubinsztein – Cambridge Institute for Medical Research
Professor Maurizio Renna - University of Naples Federico II
Dr Lars Schlotawa - University Medical Center Göttingen
Dr Christopher Wilkinson – Royal Holloway, University of London
Publications
Schlotawa L, Lopez A, Sanchez-Elexpuru G, Tyrkalska SD, Rubinsztein DC, Fleming, A (2022). A novel system for spatial and temporal control of autophagy in vivo. Autophagy
Fleming A, Xuan LZ, Sanchez-Elexpuru G, Williams SV, Windell D, Gelb MH, Herbst ZM, Schlotawa L, Rubinsztein DC (2022). Unexpected Phenotype Reversion and Survival in a Zebrafish Model of Multiple Sulfatase Deficiency. Front Cell Dev Biol. 10:843079.
Lopez A, Gorb A, Palha N, Fleming A, Rubinsztein DC (2022). A New Zebrafish Model to Measure Neuronal α-Synuclein Clearance In Vivo. Genes (Basel) 13(5):868.
Fleming A, Bourdenx M, Fujimaki M, Karabiyik C, Krause GJ, Lopez A, Martín-Segura A, Puri C, Scrivo A, Skidmore J, Son SM, Stamatakou E, Wrobel L, Zhu Y, Cuervo AM, Rubinsztein DC (2021). The Different Autophagy Degradation Pathways and Neurodegeneration. Neuron 16;110(6):935-966.
Iqbal A, Baldrighi B, Murdoch JN, Fleming A, Wilkinson CJ (2020). Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome. Biol Open 9(10):bio054338.
Fleming A, Rubinsztein DC (2020). Autophagy in Neuronal Development and Plasticity. Trends Neurosci. 43(10):767-779.
VerPlank JJS, Tyrkalska SD, Fleming A, Rubinsztein DC, Goldberg AL (2020). cGMP via PKG activates 26S proteasomes and enhances degradation of proteins, including ones that cause neurodegenerative diseases. Proc Natl Acad Sci 117(25):14220-14230.
Siddiqi FH, Menzies FM, Lopez A, Stamatakou E, Karabiyik C, Ureshino R, Ricketts T, Jimenez-Sanchez M, Esteban MA, Lai L, Tortorella MD, Luo Z, Liu H, Metzakopian E, Fernandes HJR, Bassett A, Karran E, Miller BL, Fleming A, Rubinsztein, D.C. (2019). Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nature Communications 10(1):1817.
Lopez A, Fleming A, Rubinsztein DC (2018). Seeing is believing: methods to monitor vertebrate autophagy in vivo. Open Biol. Oct 24;8(10).
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 diseases, Nat 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 disease, Nat 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 accumulation, Nat Commun, 22;5:4998
Fleming A, Diekmann H, Goldsmith P, (2013), Functional characterisation of the maturation of the blood-brain barrier in larval zebrafish, PLoS 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 fit, Drug 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
