Professor Flaviano Giorgini

Dr Flaviano Giorgini

Professor of Neurogenetics

Contact details

Tel: 0116 252 3485
Fax: +44 (0)116 252 3378
Email: fg36@le.ac.uk

 

Personal details

BSc (West Lafayette), MA (St. Louis), PhD (Seattle)

I grew up amidst the corn fields of Indiana and pursued a BSc degree in Biological Sciences (with an emphasis in Genetics) at Purdue University. I obtained a MA degree in Molecular Genetics at Washington University in Saint Louis and a PhD in Genetics at the University of Washington in Seattle. My interest in neurodegeneration research began as a Senior Fellow in the Department of Pharmacology (University of Washington). Mywork during this time, combined with my background in genetics and model organisms, formed the basis for my current research in neurogenetics at the University of Leicester. Starting as a Lecturer in the Department of Genetics in 2006, I became Reader in Neurogenetics in 2012, as has been Professor of Neurogenetics since 2015.

Teaching

Postgraduate

  • MSc Molecular Genetics Mouse as a model organism

Undergraduate Teaching

  • BS3018 Mouse transgenic technologies
  • MG3050 Huntington’s disease
  • BS1005 Genes’ – practicals

Medical School Year 1 Molecules, Genes and Disease - tutorials

Publications

Breda C, Giorgini F, Steinert, JR. Synapses and α-synuclein signalling in disease. Cogent Biology, in press.

Maddison DC, Giorgini F*. The kynurenine pathway and neurodegenerative disease. Sem Cell Dev Biol, 2015 Apr;40:134-141.

Varadarajan S, Breda C, Smalley JL, Butterworth M, Farrow S, Giorgini F, Cohen G. The transrepression arm of glucocorticoid receptor signalling is protective in mutant huntingtin-mediated neurodegeneration. Cell Death Differ, 2015 Aug;22(8):1388-96.

Breda C, Nugent ML, Estranero JG, Kyriacou CP, Outeiro TF, Steinert JR, Giorgini F*. Rab11 modulates α-synuclein mediated defects in synaptic transmission and behaviour. Hum Mol Genet 2015; 24(4):1077-91.

Mason RP, Breda C, Kooner GS, Mallucci GR, Kyriacou CP, Giorgini F*. Modelling Huntington’s disease in yeast and invertebrates. Movement Disorders: Genetics and Models, Second Edition
(Elsevier), 2015: 557 - 572.

Chutna O, Gonçalves S, Villar-Piqué A, Guerreiro P, Marijanovic Z, Mendes T, Ramalho J, Emmanouilidou E, Ventura S, Klucken J, Barral DC, Giorgini F, Vekrellis K, Outeiro TF. The small GTPase Rab11 co-localizes with α-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity. Hum Mol Genet, 2014; 23(25): 6732-45.

Zondler L, Miller-Fleming L, Repici M, Gonçalves S, Tenreiro S, Rosado-Ramos R, Betzer C, Straatman KR, Henning Jensen P, Giorgini F*, Outeiro TF*. DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson’s disease. Cell Death Dis, 2014; 5: e1350.

Yin G, Lopes da Fonseca T, Eisbach SE, Martín Anduaga A, Breda C, Karpinar DP, Orcellet ML, 
Szegő EM, Guerreiro P, Lazaro D, Braus GH , Fernandez CO, Griesinger C, Becker S, Goody RS, 
Itzen A, Giorgini F, Outeiro TF, Zweckstetter M. alpha-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. Neurobiology of Disease, 2014; 70:149-61.

Kantcheva RB, Mason RP*, Giorgini F*. Aggregation-Prone Proteins Modulate Huntingtin   Inclusion Body Formation in Yeast. PLoS Currents, 2014 Apr 23;6.

Miller-Fleming L, Antas P, Faria Pais T, Smalley JL, Giorgini F*, Outeiro TF*. Yeast DJ-1 family members are required for diauxic-shift reprogramming and cell survival in stationary phase. PNAS, 2014; 111(19): 7012-7.

Green EW, Fedele G, Giorgini F, Kyriacou CP. Widely used Drosophila RNAi collection is subject to dominant, off-target phenotypic effects. Nat Methods, 2014; 11(3):222-3.

Vittori A, Breda C, Repici M, Orth M, Roos RAC, Outeiro TF, Giorgini F, Hollox EJ and the REGISTRY investigators of the European Huntington’s Disease Network. Copy number variation of the neuronal glucose transporter gene SLC2A3 modifies the age of onset in Huntington’s disease. Hum Mol Genet, 2014 Feb 5. [Epub ahead of print].

Sajjad MU, Green EW, Miller-Fleming L, Hands S, Herrera F, Campesan S, Khoshnan A, Outeiro TF, Giorgini F, Wyttenbach A. DJ-1 modulates aggregation and pathogenesis in models of Huntington’s disease. Hum Mol Genet, 2014; 23 (3): 755-766.

Giorgini F, Huang SY, Sathyasaikumar KV, Notarangelo FM, Thomas MAR, Tararina M, Wu HQ, Schwarcz R, Muchowski PJ. Targeted Deletion of Kynurenine 3-monooxygenase (KMO) in Mice: a New Tool for Studying Kynurenine Pathway Metabolism in Periphery and Brain.  J Biol Chem, 2013; 288: 36554-36566.

Giorgini F and Steinert J. Rab11 as a modulator of synaptic transmission. Commun Integr Biol, 2013; 6(6): e26807.

Woodacre A, Lone MA, Jablonowski D, Schneiter R, Giorgini F*, Schaffrath R*. A novel Sit4 phosphatase complex is involved in the response to ceramide stress in yeast. Oxid Med Cell Longev, 2013, Article ID 129645.

Mason RP, Casu M, Butler N, Breda C, Campesan S, Clapp J, Green EW, Dhulkhed D, Kyriacou CP, Giorgini F*. Glutathione peroxidase activity is neuroprotective in models of Huntington's disease. Nat Genet, 2013; 45(10): 1249-54.

Giorgini F*. A flexible polyglutamine hinge opens new doors for understanding huntingtin function. PNAS, 2013; 110(36): 14516-7.

Giorgini F*. Understanding neuronal dysfunction and loss in neurodegenerative disease. J Mol Med (Berl), 2013; 91(6): 651-2.

Amaral M, Outeiro TF, Scrutton NS, Giorgini F*. The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease. J Mol Med (Berl), 2013; 91(6): 705-13.

Amaral M, Levy C, Heyes DJ, Lafite P, Outeiro TF, Giorgini F, Leys D, Scrutton NS. Structural basis of kynurenine 3-monooxygenase inhibition. Nature, 2013; 496(7445): 382-5.

Uthman S, Bär C, Scheidt V, Liu S, ten Have S, Giorgini F, Stark MJ, Schaffrath R. The amidation step of diphthamide biosynthesis in yeast requires DPH6, a gene identified through mining the DPH1-DPH5 interaction network. PLoS Genet, 2013; 9(2): e1003334.

Repici M, Straatman KR, Balduccio N, Enguita FJ, Outeiro TF, Giorgini F*. Parkinson's disease-associated mutations in DJ-1 modulate its dimerization in living cells. J Mol Med (Berl), 2013; 91(5): 599-611.

Kwan W, Traeger U, Davalos D, Chou A, Andre R, Miller A, Giorgini F, Cheah C, Moeller T, Stella N, Akassoglou K, Tabrizi S, Muchowski, P. J. Mutant huntingtin impairs the migration of immune cells in Huntington's disease. J Clin Invest, 2012; 122(12): 4737-47.

Green EW and Giorgini F*. Choosing and Using Drosophila Models to Characterise Modifiers of Huntington’s Disease. Biochem Soc Trans, 2012; 40(4): 739-45.

Green, EW, Campesan, S, Breda, C, Sathyasaikumar, KV, Muchowski, PJ, Schwarcz, R, Kyriacou, CP, Giorgini, F*. Drosophila eye color mutants as therapeutic tools for Huntington’s disease. Fly 2012; 6(2).

Steinert JR, Campesan S, Richards P, Kyriacou CP, Forsythe ID, and Giorgini F*. Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington’s disease. Hum Mol Genet 2012; 21(13):2912-22.

Giorgini F*. Targeting the kynurenine pathway in Huntington’s disease. Advances in Clinical Neuroscience & Rehabilitation 2012; 12(1):7-8.

Uthman S, Liu S, Giorgini F, Stark MJR, Constanzo M, Schaffrath R. Diphtheria disease and genes involved in formation of diphthamide, key effector of the diphtheria toxin. Infectious Disease (InTech) 2012; 333-356. DOI: 10.5772/31680.

Mason, RP and Giorgini, F*. Modelling Huntington disease in yeast: perspectives and future directions. Prion 2011; 1;5(4):1-8.

Campesan, S, Green, EW, Breda, C, Sathyasaikumar, KV, Muchowski, PJ, Schwarcz, R, Kyriacou, CP, Giorgini, F*. The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington’s disease. Curr Biol 2011; 7;21(11):961-6.

Zwilling D, Huang SY, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, Lee J, Truong J, Andrews-Zwilling Y, Hsieh EW, Louie JY, Wu T, Scearce-Levie K, Patrick C, Adame A, Giorgini F, Moussaoui S, Laue G, Rassoulpour A, Flik G, Huang Y, Muchowski JM, Masliah E, Schwarcz R, Muchowski PJ. Kynurenine 3-monoxygenase inhibition in blood ameliorates neurodegeneration. Cell 2011; 10;145(6):863-74.

Giorgini F*. Is modulating translation a therapeutic option for Huntington’s disease? Neurodegen Dis Manage 2011; 1(2), 89-91.

Tauber E, Miller-Fleming L, Mason RP, Kwan W, Clapp J, Butler NJ, Outeiro TF, Muchowski PJ, Giorgini F*. Functional gene expression profiling in yeast implicates translational dysfunction in mutant huntingtin toxicity. J Biol Chem 2011; 286(1):410-9.Richards P, Didszun C, Campesan S, Simpson A, Horley B, Young KW, Glynn P, Cain K, Kyriacou CP, Giorgini F, Nicotera P. Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington’s disease. Cell Death Differ, in press.

Thevandavakkam MA, Schwarcz R, Muchowski PJ, Giorgini F*. Targeting
kynurenine 3-monooxygenase (KMO): Implications for therapy in Huntington's disease. CNS & Neurological Disorders - Drug Targets, in press.

Hands SL, Mason R, Sajjad MU, Giorgini F, Wyttenbach A. Metallothioneins and copper metabolism are candidate therapeutic targets in Huntington’s disease. Biochem Soc Trans, 2010; 38(2):552-8.

Wacker JL, Huang SY, Steele AD, Aron R, Lotz GP, Nguyen Q, Giorgini F, Roberson ED, Lindquist S, Masliah E, Muchowski PJ. Loss of Hsp70 exacerbates pathogenesis but not levels of fibrillar aggregates in a mouse model of Huntington's disease. J Neurosci. 2009; 29(28):9104-14.

Giorgini F and Muchowski PJ. Exploiting yeast genetics to inform therapeutic strategies for Huntington’s disease. Methods Mol Biol. 2009;548:161-74.

Giorgini F*. The kynurenine pathway and microglia: Implications for pathology and therapy in Huntington's disease. Protein Misfolding in Biology and Disease (Research Signpost). 2008; 978-81.

Miller-Fleming L, Giorgini F, Outeiro TF. Yeast as a Model for Studying Human Neurodegenerative Disorders. Biotechnol J. 2008; 3(3): 325-38.

Giorgini F, Möller T, Wacker JL, Hong S, Tsai LC, Cheah CS, Schwarcz R, Guidetti P, Muchowski PJ. Histone Deacetylases Modulate Activation of the Kynurenine Pathway in Yeast, Microglia and Mice Expressing a Mutant Huntingtin Fragment. J Biol Chem. 2007; 283(12):7390-400.

Duennwald M, Jagadish S, Giorgini F, Muchowski PJ, Lindquist SL. A network of protein interactions determines polyglutamine toxicity. Proc Natl Acad Sci U S A. 2006; 103(29):11051-6.

Giorgini F and Muchowski PJ. Screening for genetic modifiers of amyloid toxicity in yeast. Methods Enzymol. 2006; 412:201-22.

Outeiro TF and Giorgini F*. Yeast as a drug discovery platform in Huntington's and Parkinson's diseases. Biotechnol J. 2006, 1: 270-281.

Giorgini F, Guidetti P, Nguyen QV, Bennett SC, Muchowski PJ. A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nat Genet. 2005, 37(5):526-531.

Giorgini F, and Muchowski PJ. Connecting the dots in Huntington disease: exploiting a protein interaction network. Genome Biol. 2005, 6(3):210.1-210.5.

*Corresponding author.

Research

Huntington's disease (HD) is a fatal neurodegenerative disorder inherited in an autosomal dominant manner. This disease is caused by an expansion of a polyglutamine tract in the protein huntington and is characterised by atrophy in the striatum and cortex of the brain. The most common symptomatic manifestations of the disease are chorea (involuntary jerking of muscles), cognitive deficits and psychiatric disturbances. Although the initiating trigger in HD is known, the critical molecular mechanisms underlying this devastating illness remain unresolved. Our work focuses on elucidating these molecular mechanisms with the hope of aiding in the development of therapeutic strategies for HD.

Parkinson's disease (PD) is the second most common neurodegenerative disorder in the Western world after Alzheimer’s disease and is characterised by dopaminergic cellParkinsons Disease loss in the substantia nigra and the presence of cytoplasmic proteinaceous inclusions called Lewy bodies. Depletion of dopamine in the striatum causes deregulation of the motor circuits that project throughout the basal ganglia, resulting in the clinical manifestations of PD (resting tremor, slowness of movement, muscular rigidity, and postural instability). The vast majority of PD cases are thought to be idiopathic but 5-10 per cent are due to a genetic component, showing both dominant and recessive modes of inheritance. Linkage data has identified ten loci, named PARK, and mutations in several genes have already been mapped.

Our work, in collaboration with Dr Tiago Outeiro (IMM, Lisbon), is focused on DJ-1 (PARK7). We are using mammalian cell, Drosophila and yeast models of HD and PD to characterise conserved mechanisms and genes involved in pathology of these diseases, with the ultimate goal of identifying novel therapeutic targets.

A good deal of our research is focused on the role of the kynurenine pathway in HD pathology, and we have a particular interest in the enzyme kynurenine 3-monoxygenase (KMO) as a candidate therapeutic target for this disease.

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Contact Details

Department of Genetics
University of Leicester

Adrian Building
University Road
Leicester
LE1 7RH
United Kingdom
 

Tel: +44 (0)116 252 3374

Fax: +44 (0)116 252 3378

E Mail: genetics@le.ac.uk

 

Interim Head of Department

Professor Alison Goodall