Professor Giovanna Mallucci FMedSci University positionProfessor Professor Giovanna Mallucci FMedSci is pleased to consider applications from prospective PhD students. DepartmentsDepartment of Clinical Neurosciences InstitutesUK Dementia Research Institute at University of Cambridge Home pagehttps://ukdri.ac.uk/centres... (personal home page) Research ThemesInterestsMy lab is interested in understanding mechanisms of neurodegeneration. The central theme is the identification of common pathways across the spectrum of these disorders (which include Alzheimer's and related diseases) that are relevant for both mechanistic insights and therapy. We focus both on ‘toxic’ processes that can be targeted to prevent neuronal death, and on regenerative processes that can be harnessed for repair. Using mouse models, we described the pathogenic role of the unfolded protein response (UPR) in neurodegeneration, which led to the discovery of the first small molecule - an inhibitor of this pathway - to prevent neurodegeneration in vivo. We also recently discovered the phenomenon of failure of synaptic repair processes in neurodegeneration and the underlying mechanisms: failure of another stress response involving 'cold shock' proteins, which we have successfully harnessed for neuroprotection. We aim to translate this research for new treatments for dementia.  mechanisms of neurodegeneration and synaptic regeneration View image full-size (5683x4183 pixels) Research Focus
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Associated News Items
Key publicationsHughes DT, Halliday M, Smith HL, Verity NC, Molloy C, Radford H, Butcher AJ, Mallucci GR (2020), “Targeting the kinase insert loop of PERK selectively modulates PERK signaling without systemic toxicity in mice.” Science Signaling 11;13(644):eabb4749 PDF Smith H, Freeman OJ, Butcher AJ, Holmqvist S, Humoud I, Schätzl T, Hughes DT, Verity NC, Swinden DP, Hayes J, de Weerd L, Rowitch DH, Franklin RJM, Mallucci GR (2020), “Astrocytic UPR causes non-cell autonomous neurotoxicity and represents new therapeutic target for neurodegenerative disease. ” Neuron S0896-6273(19)31056-6 PDF Halliday M, Radford H, Zents KAM, Verity NC, Smith E, Ortori CA, Barrett DA, Bushell M, Mallucci GR (2017), “Repurposed drugs targeting eIF2?-P-mediated translational repression prevent neurodegeneration in mice. ” Brain 140(6):1768-1783 PDF Peretti D, Bastide A, Radford H, Verity N, Molloy C, Martin MG, Moreno JA, Steinert JR, Smith T, Dinsdale D, Willis AE, Mallucci GR (2015), “RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration.” Nature 518(7538):236-9 PDF Details Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, Mallucci GR (2013), “Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice.” Sci Transl Med 5(206):206ra138 PDF Details Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR (2012), “Sustained translational repression by eIF2?-P mediates prion neurodegeneration.” Nature 485(7399):507-11 PDF Details Mallucci G, Dickinson A, Linehan J, Klöhn PC, Brandner S, Collinge J (2003), “Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis.” Science 302(5646):871-4 PDF Details Publications2021Peretti DA, Smith, HL, Verity N, Humoud I, de Weerd L, Swinden DP, Hayes J, Mallucci GR (2021), “TrkB signaling regulates RBM3-mediated neuroprotection. ” Science Alliance 4(4) e202000884 doi: 10.26508/lsa.202000884 2019Cagnetta E, Wong HH, Free CK, Mallucci GR, Krijgsveld J, Holt CE (2019), “Non-canonical modulation of eIF2 pathway controls increase in local translation during neural wiring.” Molecular Cell 7;73(3):474-489.e5l doi.org /10.1016/ j.molcel.2018.11.013 2018Restelli LM, Oettinghaus B, Halliday M, Agca C, Licci M, Sironi L, Savoia C, Hench J, Tolnay M, Neutzner A, Schmidt A, Eckert A, Mallucci GR, Scorrano L, Frank S (2018), “Neuronal mitochondrial dysfunction activates the Integrated Stress Response to induce Fibroblast Growth Factor 21. ” Cell Reports 24:1407-1414 PDF Robinson SW, Bourgognon JM, Spiers JG, Breda C, Campesan S, Butcher A, Mallucci GR, Dinsdale D, Morone N, Mistry R, Smith TM, Guerra-Martin M, Challiss RAJ, Giorgini F, Steinert JR (2018), “Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability.” PLoS Biology 16(4) e2003611 PDF 2017Bastide A, Peretti D, Knight JRP, Grosso S, Spriggs RV, Pichon X, Sbarrato T, Roobol A, Roobol J, Vito D, Bushell M, von der Haar T, Smales CM, Mallucci GR, Willis AE (2017), “RTN3, a novel cold-induced protein, mediates the neuroprotective effects of RBM3.” Current Biology 27(5):638-650 PDF 2016Bradley S, Bourgognon JM, Sanger H, Verity N, Mogg A, White D, Butcher A, Moreno JA, Molloy C, Macedo-Hatch T, Edwards J, Wess J, Pawlak R, Read DJ, Sexton P, Broad L, Steinert J, Mallucci GR, Christopoulos A, Felder C, Tobin AB (2016), “M1-muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.” Journal of Clinical Investigation 87526 PDF Celardo I, Costa A, Lehmann S, Jones C, Wood N, Mencacci N, Mallucci GR, Loh S, Martins LMM (2016), “Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease.” Cell Death & Disease 6:e2271 PDF Knight JR, Bastide A, Peretti D, Roobol A, Roobol J, Mallucci GR, Smales CM, Willis AE (2016), “Cooling-induced SUMOylation of EXOSC10 down-regulates ribosome biogenesis.” RNA 22(4):623-35 PDF 2015Halliday M, Mallucci GR (2015), “Review: Modulating the unfolded protein response to prevent neurodegeneration and enhance memory.” Neuropathol Appl Neurobiol 41(4):414-27 PDF Details Halliday M, Radford H, Sekine Y, Moreno J, Verity N, le Quesne J, Ortori CA, Barrett DA, Fromont C, Fischer PM, Harding HP, Ron D, Mallucci GR (2015), “Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity.” Cell Death Dis 6:e1672 PDF Details Radford H, Moreno JA, Verity N, Halliday M, Mallucci GR (2015), “PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia.” Acta Neuropathologica 130(5):633-42. PDF 2014Brinkmalm A, Brinkmalm G, Honer WG, Moreno JA, Jakobsson J, Mallucci GR, Zetterberg H, Blennow K, Öhrfelt A (2014), “Targeting synaptic pathology with a novel affinity mass spectrometry approach.” Mol Cell Proteomics 13(10):2584-92 Details Halliday M, Mallucci GR (2014), “Targeting the unfolded protein response in neurodegeneration: A new approach to therapy.” Neuropharmacology 76 Pt A:169-74 PDF Details Halliday M, Radford H, Mallucci GR (2014), “Prions: generation and spread versus neurotoxicity.” J Biol Chem 289(29):19862-8 Details Tufi R, Gandhi S, de Castro IP, Lehmann S, Angelova PR, Dinsdale D, Deas E, Plun-Favreau H, Nicotera P, Abramov AY, Willis AE, Mallucci GR, Loh SH, Martins LM (2014), “Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson's disease.” Nat Cell Biol 16(2):157-66 PDF Details 2013Dhiraj DK, Chrysanthou E, Mallucci GR, Bushell M (2013), “miRNAs-19b, -29b-2* and -339-5p show an early and sustained up-regulation in ischemic models of stroke.” PLoS One 8(12):e83717 Details Halliez S, Chesnais N, Mallucci G, Vilotte M, Langevin C, Jaumain E, Laude H, Vilotte JL, Béringue V (2013), “Targeted knock-down of cellular prion protein expression in myelinating Schwann cells does not alter mouse prion pathogenesis.” J Gen Virol 94(Pt 6):1435-40 Details Mallucci G (2013), “Spreading proteins in neurodegeneration: where do they take us?” Brain 136(Pt 4):994-5 Details 2011Verity NC, Mallucci GR (2011), “Rescuing neurons in prion disease.” Biochem J 433(1):19-29 Details 2010Moreno JA, Mallucci GR (2010), “Dysfunction and recovery of synapses in prion disease: implications for neurodegeneration.” Biochem Soc Trans 38(2):482-7 Details Radford HE, Mallucci GR (2010), “The role of GPI-anchored PrP C in mediating the neurotoxic effect of scrapie prions in neurons.” Curr Issues Mol Biol 12(2):119-27 Details 2009Mallucci GR (2009), “Can mutations of prion protein shed light on its normal function?” J Neurol Neurosurg Psychiatry 80(12):1303 Details Mallucci GR (2009), “Prion neurodegeneration: starts and stops at the synapse.” Prion 3(4):195-201 Details White MD, Mallucci GR (2009), “RNAi for the treatment of prion disease: a window for intervention in neurodegeneration?” CNS Neurol Disord Drug Targets 8(5):342-52 Details White MD, Mallucci GR (2009), “Therapy for prion diseases: Insights from the use of RNA interference.” Prion 3(3):121-8 Details 2008White MD, Farmer M, Mirabile I, Brandner S, Collinge J, Mallucci GR (2008), “Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion disease.” Proc Natl Acad Sci U S A 105(29):10238-43 PDF Details 2007Mallucci GR, White MD, Farmer M, Dickinson A, Khatun H, Powell AD, Brandner S, Jefferys JG, Collinge J (2007), “Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice.” Neuron 53(3):325-35 PDF Details 2006Nassar MA, Baker MD, Levato A, Ingram R, Mallucci G, McMahon SB, Wood JN (2006), “Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice.” Mol Pain 2:33 Details 2005Mallucci G, Collinge J (2005), “Rational targeting for prion therapeutics.” Nat Rev Neurosci 6(1):23-34 PDF Details 2004Mallucci G, Collinge J (2004), “Update on Creutzfeldt-Jakob disease.” Curr Opin Neurol 17(6):641-7 Details 2002Mallucci GR, Ratté S, Asante EA, Linehan J, Gowland I, Jefferys JG, Collinge J (2002), “Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration.” EMBO J 21(3):202-10 PDF Details 1999Mallucci GR, Campbell TA, Dickinson A, Beck J, Holt M, Plant G, de Pauw KW, Hakin RN, Clarke CE, Howell S, Davies-Jones GA, Lawden M, Smith CM, Ince P, Ironside JW, Bridges LR, Dean A, Weeks I, Collinge J (1999), “Inherited prion disease with an alanine to valine mutation at codon 117 in the prion protein gene.” Brain 122 ( Pt 10):1823-37 Details |
