Luca Muzio RicercatoreMedicine
Protein aggregation and misfolding likely contribute to neuronal loss in Alzheimer’ disease, Parkinson’ disease and Amyotrophic Lateral Sclerosis. Indeed, neurons cannot divide and therefore they cannot dilute these toxic substances at each round of cell division. Therefore, these toxic substrates accumulate in neurons and finally they overwhelm pathways involved in their clearance/degradation. Thus, the presence of proteinaceous aggregates, often hijacked in neuronal cytoplasmic inclusions, is a pathological hallmark of these disorders. Central for the development of new therapeutic strategies for the treatment of these proteinopathy-driven diseases is the study of molecular machineries that counteract the accumulation of these aggregates, such as the ubiquitin-proteasome system, the autophagy-lysosomal pathway, the retromer/retriever system.
Our laboratory has a great interest to investigate these pathways using animal models of these disorders as well as human iPSCs-derived neurons established from fibroblasts of patients. Capitalizing our knowledge about these detrimental processes, we have:
- identified new therapeutic molecules that modulate the autophagic flux in neurons
- developed new molecular chaperones that stabilize the retromer complex in vitro and in vivo, improving the lysosomal flux and the homeostasis of neurons
- designed, synthetized and validated new chimeric proteins that regulate the expression levels of inflammatory cues that associate with these neurodegenerative processes.
1989-1996 Degree in Biology, University of Genoa; Genoa, Italy
2000-2005 PhD in Molecular and Cellular Biology (Open University of London)
1993-1996. Undergraduate student Institute for Cancer Research, Genoa, Italy
1996-1997. Postgraduate student, Advanced Biotechnology Center, Genoa, Italy
1997-1998. Postgraduate student, San Raffaele Scientific Institute, Milan, Italy
1998-2005. PhD fellowship, San Raffaele Scientific Institute, Milan, Italy.
2006-2007. Post-Doc San Raffaele Scientific Institute, Milan, Italy.
2007-at present. Research Associate San Raffaele Scientific Institute, Milan, Italy.
From 2005 at present, PhD student supervisor of International Ph.D Program in Cellular and Molecular Biology and International Graduate School in Molecular Medicine, Vita & Salute San Raffaele University, Milan, Italy
From 2015 at present. Professor on contract at Vita & Salute San Raffaele University, faculty of Biotechnology and Medical Biology.
- Fism 2005/R/15, 2006- 2008, research project. Title of the project: Study of the molecular and cellular characteristics of the developmental pathways involved in neural stem/precursor cell-mediated regenerative processes occurring during experimental multiple sclerosis.
- NMSS 4016A2, 2008-2011, research project. Title of the project: The role of endogenous neural stem/precursor cells in multiple sclerosis.
- PRIN R0345, 2008-2010. Title of the project: Study of the therapeutic potential of adult neural stem cells in acute and chronic inflammatory disorder of the central and peripheral nervous system.
- Contratto Teva Italia Laquinimod SR1409 2009-2011.
- Fism 2009/R/18 2010-2011 research projects. Title of the project: Study of the mechanism/s of neuronal degeneration during inflammatory demyelinating disorders.
- Arisla 2012 pilot project. Title of the project: ALS, the role of microglia, astrocytes and inflammation (ASL MAI).
- Grant Merk-Serono 2011-2013 research project. Title of the project: Microglia in MS
- Grant Merk-Serono 2013-2016 research project. Title of the project: Microglia in MS
- Grant Fondazione Veronesi 2014-2016. Title of the project: Role of Asics and acidosis in iSchemic Stroke of the aged (RAISS).
- Fism 2014/R/18 2014 – 2016, research project. Title of the project: ACidosis in CNS Inflammatory DIseases: the role of Asics channels (ACCIDIA).
- Seed grant OSR 2016 - 2019 research project. Title of the project: Misfolded protein in Amyotrophic Lateral Sclerosis (MALvaSIA).
- Fism 2018/R/12, 2019 - 2020, research project. Title of the project: "Sviluppo di proteine REcTO per modulare la neuroinfiammazione".
- Arisla 2020-2022 research project. Title of the project: Retromer complex in ALS
- FRRB 2019-2022, research project. Title of the project: New frontiers of engineered nanovectors to improve treatment efficacy and safety in neurological disorders.
- Boncinelli, E., A. Mallamaci, and L. Muzio, Genetic control of regional identity in the developing vertebrate forebrain. Novartis Foundation symposium, 2000. 228: p. 53-61; discussion 61-6, 109-13.
- Mallamaci, A., et al., The lack of Emx2 causes impairment of Reelin signaling and defects of neuronal migration in the developing cerebral cortex. Journal of Neuroscience, 2000. 20(3): p. 1109-1118.
- Mallamaci, A., et al., Area identity shifts in the early cerebral cortex of Emx2-/- mutant mice. Nature neuroscience, 2000. 3(7): p. 679-686.
- Galli, R., et al., Emx2 regulates the proliferation of stem cells of the adult mammalian central nervous system. Development, 2002. 129(7): p. 1633-1644.
- Muzio, L., et al., Conversion of cerebral cortex into basal ganglia in Emx2(-/-) Pax6(Sey/Sey) double-mutant mice. Nature neuroscience, 2002. 5(8): p. 737-745.
- Muzio, L., et al., Emx2 and Pax6 control regionalization of the pre-neuronogenic cortical primordium. Cerebral Cortex, 2002. 12(2): p. 129-139.
- Muzio, L. and A. Mallamaci, Emx1, Emx2 and Pax6 in specification, regionalization and arealization of the cerebral cortex. Cerebral Cortex, 2003. 13(6): p. 641-647.
- Muzio, L. and A. Mallamaci, Foxg1 confines Cajal-Retzius neuronogenesis and hippocampal morphogenesis to the dorsomedial pallium. Journal of Neuroscience, 2005. 25(17): p. 4435-4441.
- Gangemi, R.M.R., et al., Effects of Emx2 inactivation on the gene expression profile of neural precursors. European Journal of Neuroscience, 2006. 23(2): p. 325-334.
- Muzio, L., G. Martino, and R. Furlan, Multifaceted aspects of inflammation in multiple sclerosis: The role of microglia. Journal of Neuroimmunology, 2007. 191(1-2): p. 39-44.
- 15. Pluchino, S., et al., Persistent inflammation alters the function of the endogenous brain stem cell compartment. Brain: a journal of neurology, 2008. 131: p. 2564-2578.
- Centonze, D., et al., Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis. Journal of Neuroscience, 2009. 29(11): p. 3442-3452.
- Rossi, S., et al., Exercise attenuates the clinical, synaptic and dendritic abnormalities of experimental autoimmune encephalomyelitis. Neurobiology of disease, 2009. 36(1): p. 51-59.
- Muzio, L., et al., Cxcl10 enhances blood cells migration in the sub-ventricular zone of mice affected by experimental autoimmune encephalomyelitis. Molecular and Cellular Neuroscience, 2010. 43(3): p. 268-280.
- Rossi, S., et al., Abnormal activity of the Na/Ca exchanger enhances glutamate transmission in experimental autoimmune encephalomyelitis. Brain Behavior and Immunity, 2010. 24(8): p. 1379-1385.
- Schiering, C., et al., Antigen-Experienced CD4(+) T Cells Limit Naive T-Cell Priming in Response to Therapeutic Vaccination In vivo. Cancer Research, 2010. 70(15): p. 6161-6170.
- Marinaro, C., et al., In Vivo Fate Analysis Reveals the Multipotent and Self-Renewal Features of Embryonic AspM Expressing Cells. PloS one, 2011. 6(4).
- Rossi, S., et al., Cannabinoid CB1 receptors regulate neuronal TNF-alpha effects in experimental autoimmune encephalomyelitis. Brain Behavior and Immunity, 2011. 25(6): p. 1242-1248.
- Rossi, S., et al., Impaired striatal GABA transmission in experimental autoimmune encephalomyelitis. Brain Behavior and Immunity, 2011. 25(5): p. 947-956.
- Arno, B., et al., Microglial cells during forebrain development. Journal of Neuroimmunology, 2012. 253(1-2): p. 66-66.
- 26. Bianchi, V., et al., Forebrain Deletion of alpha GDI in Adult Mice Worsens the Pre-Synaptic Deficit at Cortico-Lateral Amygdala Synaptic Connections. PloS one, 2012. 7(1).
- Butti, E., et al., Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitotoxicity. Brain : a journal of neurology, 2012. 135: p. 3320-3335.
- Capossela, S., et al., Growth Defects and Impaired Cognitive-Behavioral Abilities in Mice with Knockout for Eif4h, a Gene Located in the Mouse Homolog of the Williams-Beuren Syndrome Critical Region. American Journal of Pathology, 2012. 180(3): p. 1121-1135.
- Florio, M., et al., Neurogenin 2 regulates progenitor cell-cycle progression and Purkinje cell dendritogenesis in cerebellar development. Development, 2012. 139(13): p. 2308-2320.
- Marinaro, C., et al., Wnt Signaling Has Opposing Roles in the Developing and the Adult Brain That Are Modulated by Hipk1. Cerebral Cortex, 2012. 22(10): p. 2415-2427.
- Rossi, S., et al., Interleukin-1 beta causes synaptic hyperexcitability in multiple sclerosis. Annals of neurology, 2012. 71(1): p. 76-83.
- Verderio, C., et al., Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Annals of neurology, 2012. 72(4): p. 610-624.
- Laterza, C., et al., iPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF. Nature communications, 2013. 4.
- Muzio, L. and G.G. Consalez, Modeling human brain development with cerebral organoids. Stem Cell Research & Therapy, 2013. 4.
- Serafini, B., et al., Radioactive in situ hybridization for Epstein-Barr virus-encoded small RNA supports presence of Epstein-Barr virus in the multiple sclerosis brain. Brain: a journal of neurology, 2013. 136.
- Arno, B., et al., Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex. Nature communications, 2014. 5.
- Onorati, M., et al., Molecular and functional definition of the developing human striatum. Nature neuroscience, 2014. 17(12): p. 1804-1815.
- Rossi, C., et al., The role of Microglia and Inflammation in an animal model Of ALS. Journal of Neuroimmunology, 2014. 275(1-2): p. 170-171.
- de Ceglia, R., et al., Down-sizing of neuronal network activity and density of presynaptic terminals by pathological acidosis are efficiently prevented by Diminazene Aceturate. Brain Behavior and Immunity, 2015. 45: p. 263-276.
- Bacigaluppi, M., et al., Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes. Journal of Neuroscience, 2016. 36(41): p. 10529-10544.
- Casella, G., et al., IL4 induces IL6-producing M2 macrophages associated to inhibition of neuroinflammation in vitro and in vivo. Journal of Neuroinflammation, 2016. 13.
- Mazzocchi, N., et al., Fluorescence-Based Automated Screening Assay for the Study of the pH-Sensitive Channel ASIC1a. Journal of Biomolecular Screening, 2016. 21(4): p. 372-380.
- Medelin, M., et al., Altered development in GABA co-release shapes glycinergic synaptic currents in cultured spinal slices of the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Journal of Physiology-London, 2016. 594(13): p. 3827-3840.
- Muzio, L., et al., Increased neuroplasticity and hippocampal microglia activation in a mice model of rapid antidepressant treatment. Behavioural Brain Research, 2016. 311: p. 392-402.
- Penton-Rol, G., et al., Comparative Neuroregenerative Effects of C-Phycocyanin and IFN-Beta in a Model of Multiple Sclerosis in Mice. Journal of Neuroimmune Pharmacology, 2016. 11(1): p. 153-167.
- Casella, G., et al., IL-27, but not IL-35, inhibits neuroinflammation through modulating GM-CSF expression. Scientific reports, 2017. 7.
- Casella, G., et al., Extracellular Vesicles Containing IL-4 Modulate Neuroinflammation in a Mouse Model of Multiple Sclerosis. Molecular Therapy, 2018. 26(9): p. 2107-2118.
- Castiglioni, V., et al., Dynamic and Cell-Specific DACH1 Expression in Human Neocortical and Striatal Development. Cerebral cortex 2019 May; 29(5): 2115–2124
- Cusimano, M., et al., Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury. Journal of Neuroinflammation, 2018. 15.
- Guarnieri, F.C., et al., Synapsin I deletion reduces neuronal damage and ameliorates clinical progression of experimental autoimmune encephalomyelitis. Brain Behavior and Immunity, 2018. 68: p. 197-210.
- Rossi, C., et al., Interleukin 4 modulates microglia homeostasis and attenuates the early slowly progressive phase of amyotrophic lateral sclerosis. Cell Death & Disease, 2018. 9.
- Spinelli, A., et al., Intracisternal delivery of PEG-coated gold nanoparticles results in high brain penetrance and long-lasting stability. Journal of nanobiotechnology, 2019. 17(1): p. 49-49.
- Francesca Grassivaro, Ramesh Menon, Massimo Acquaviva, Linda Ottoboni, Francesca Ruffini, Andrea Bergamaschi, Luca Muzio, Cinthia Farina, and Gianvito Martino. Convergence between microglia and peripheral macrophages phenotype during development and neuroinflammation. Journal of Neuroscience, 2 January 2020, 40 (4) 784-795.
- Luca Muzio, Riccardo Sirtori, Davide Gornati, Simona Eleuteri, Andrea Fossaghi, Diego Brancaccio, Leonardo Manzoni, Linda Ottoboni, Luca De Feo, Angelo Quattrini, Eloise Mastrangelo, Luca Sorrentino, Emanuele Scalone, Giancarlo Comi, Luciana Marinelli, Nilo Riva, Mario Milani, Pierfausto Seneci, Gianvito Martino. Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis. Nat Commun. 2020 Jul 31;11(1):3848. doi: 10.1038/s41467-020-17524-7.
- Davide Gornati, Roselia Ciccone, Antonio Vinciguerra, Stefania Ippati, Anna Pannaccione, Tiziana Petrozziello, Erika Pizzi, Amal Hassan, Eleonora Colombo, Stefano Barbini, Mario Milani, Cecilia Caccavone, Pietro Randazzo, Luca Muzio, Lucio Annunziato, Andrea Menegon, Agnese Secondo, Eloise Mastrangelo, Giuseppe Pignataro and Pierfausto Seneci. Synthesis and Characterization of Novel Mono- and Bis-Guanyl Hydrazones as Potent and Selective ASIC1a Inhibitors Able to Reduce Brain Ischemic Insult. Journal of Medicinal Chemistry, 2021 in press
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