Proteomic of iron metabolism
The unit studied, from a functional, structural and immunological standpoint, proteins involved in iron metabolism and diseases associated with them. In recent years, the main research lines followed in the unit are focused to the study of mitochondrial iron metabolism and the understanding of the role of iron in neurodegenerative processes.
More recently the group dealt with the development of cellular and animal models for the study of diseases characterized by the presence of brain iron accumulation, or NBIA (Neurodegeneration with Brain Iron Accumulation). Several genes have been identified as causative of NBIA, pathologies classified as extrapiramidal movement disorders with variable age of onset. The aim is to identify, from the different forms of NBIA, the probable common pathological events that give rise to the brain iron accumulation phenotype. Presently the group is studying the iron metabolism alterations in patients suffering from PKAN, which is the most frequent form between the NBIA and caused by mutation in PANK2. Also neuroferritinopathy is examined, which is caused by mutations in the ferritin L gene.
The unit is using the cellular reprogramming methodologies to develop new human neuronal models, useful to examine the alteration of the iron metabolism in these pathologies. Proteominc of iron metabolism Unit obtained and characterized neurons induced pluripotent stem cells (hiPSC) derived from patients suffering from PKAN and neuroferritinopathy. These new models represent a powerful in vitro model system in which to investigate and dissect early molecular events, eventually accumulating and giving rise to degeneration or death of neuronal cells. These studies allow to identify possible therapeutic targets and to test in vitro efficacy of specific compounds.
Guaraldo M, Santambrogio P, Rovelli E, Di Savino A, Saglio G, Cittaro D, Roetto A, Levi S. Characterization of human mitochondrial ferritin promoter identification of transcription factors and evidences of epigenetic control. Sci. Rep. 2016; 6: 33432.
Orellana Di, Santambrogio P, Rubio A, Yekhlef L, Cancellieri C, Dusi S, Giannelli Sg, Venco P, Mazzara Pg, Cozzi A, Ferrari M, Garavaglia B, Taverna S, Tiranti V, Broccoli V, Levi S. Coenzyme a corrects pathological defects in human neurons of pank2- associated neurodegeneration. Embo Mol Med. 2016 Oct 4;8(10):1197-1211.
Maccarinelli F, Pagani A, Cozzi A, Codazzi F, Di Giacomo G, Capoccia S, Rapino S, Finazzi D, Politi LS, Cirulli F, Giorgio M, Cremona O, Grohovaz F, Levi S. A novel neuroferritinopathy mouse model (ftl 498instc) shows progressive brain iron dysregulation, morphological signs of early neurodegeneration and motor coordination deficits. Neurobiol Dis. 2015;81:119-33.
Levi S, Rovida E. Neuroferritinopathy: from ferritin structure modification to pathogenetic mechanism. Neurobiol Dis. 2015 Sep;81:134-43.
Santambrogio P, Dusi S, Guaraldo M, Rotundo LI, Broccoli V, Garavaglia B, Tiranti V, Levi S. Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients. Neurobiol Dis. 2015 Sep;81:144-53.
Levi S, Finazzi D. Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms. Front Pharmacol. 2014 May 7;5:99.
Levi S, Taveggia C. Iron homeostasis in peripheral nervous system, still a black box? Antioxid Redox Signal. 2014 Aug 1;21(4):634-48.
Cozzi A, Santambrogio P, Privitera D, Broccoli V, Rotundo LI, Garavaglia B, Benz R, Altamura S, Goede JS, Muckenthaler MU, Levi S. Human l- ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome. J Exp Med. 2013;210(9):1779-91.
Campanella A, Privitera D, Guaraldo M, Rovelli E, Barzaghi C, Garavaglia B, Santambrogio P, Cozzi A, Levi S. Skin fibroblasts from pantothenate kinase-associated neurodegeneration patients show altered cellular oxidative status and have defective iron-handling properties. Hum Mol Genet. 2012 Sep 15;21(18):4049-59.
Santambrogio P, Erba BG, Campanella A, Cozzi A, Causarano V, Cremonesi L, Gallì A, Della Porta MG, Invernizzi R, Levi S. Over- expression of mitochondrial ferritin affects the jak2/stat5 pathway in k562 cells and causes mitochondrial iron accumulation. Haematologica 2011;96(10):1424-32.