The work of Cellular neurophysiology Unit is aimed at understanding the molecular and cellular mechanisms underlying neuroprotection, neuroinflammation and neurodegeneration. Final objective is the identification of biomarkers and pharmacological targets for the prevention and cure of neurodegenerative diseases.
The brain is particularly vulnerable to toxic effects of reactive oxygen species and a clear correlation with neurodegeneration has been observed. This group is interested in the way oxidative stress is generated and protection mechanisms are activated in both neurons and astrocytes. In light of the relevance of neuroinflammatory processes in neurodegeneration, group interest is also focused on the molecular mechanisms involved in the process of glia activation and on the influence the activated phenotype has on neuronal survival.
It is well known that an increase in synaptic activity is potentially harmful for neurons, determining dysregulation of the ionic homeostasis as well as alterations of protein expression. In this respect, iron is an essential element required for many physiological functions, but it is also a key player in oxidative stress induction. Of note, iron accumulation within neurons is a condition that occurs physiologically with age but is also favoured in many neurodegenerative diseases.
A research line of this lab is aimed at characterizing the physiological mechanisms of iron handling, at both cellular and mitochondrial level, in primary neurons and glial cells. Moreover, Induced Pluripotent Stem Cells (iPSCs) are employed in investigating the molecular mechanisms underlying Friedreich’s ataxia, as well as other neurodegenerative disorders characterized by alteration of intracellular iron homeostasis.
In another research line, this group investigates the effect of increased synaptic activity on the control of BACE1, the beta-secretase that triggers the amyloidogenic processing of the amyloid precursor protein thereby favouring deposition of the neurotoxic amyloid-beta peptide in the brain of Alzheimer’s disease patients. It has been provided evidence that BACE-1 expression is tightly regulated and that, even in the absence of an increase in the transcript, its expression can be controlled by translational regulation. The Unit is currently characterizing an initiation factor that is preferentially localized at synaptic microdomains and that is able to regulate the translation initiation of BACE1 in response to increased synaptic activity.
Codazzi F, Hu A, Rai M, Donatello S, Salerno Scarzella F, Mangiameli E, Pelizzoni I, Grohovaz F, Pandolfo M. Friedreich ataxia-induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor. Hum Mol Genet. 2016 Nov 15;25(22):4847-4855.
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 Sep;81:119-33.
Macco R, Pelizzoni I, Consonni A, Vitali I, Giacalone G, Martinelli Boneschi F, Codazzi F, Grohovaz F, Zacchetti D. Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation. J Neuroinflammation. 2013 Oct 28;10:130.
Pelizzoni I, Zacchetti D, Smith CP, Grohovaz F, Codazzi F. Expression of divalent metal transporter 1 in primary hippocampal neurons: reconsidering its role in non-transferrin-bound iron influx. J Neurochem. 2012 Jan;120(2):269-78.
Pelizzoni I, Macco R, Morini MF, Zacchetti D, Grohovaz F, Codazzi F. Iron handling in hippocampal neurons: activity-dependent iron entry and mitochondria-mediated neurotoxicity. Aging Cell. 2011 Feb;10(1):172-83.
Mihailovich M, Thermann R, Grohovaz F, Hentze MW, Zacchetti D. Complex translational regulation of BACE1 involves upstream AUGs and stimulatory elements within the 5' untranslated region. Nucleic Acids Res. 2007;35(9):2975-85.
Di Cesare A, Del Piccolo P, Zacchetti D, Grohovaz F. EP2 receptor stimulation promotes calcium responses in astrocytes via activation of the adenylyl cyclase pathway. Cell Mol Life Sci. 2006 Nov;63(21):2546-53.
Codazzi F, Di Cesare A, Chiulli N, Albanese A, Meyer T, Zacchetti D, Grohovaz F. Synergistic control of protein kinase Cgamma activity by ionotropic and metabotropic glutamate receptor inputs in hippocampal neurons. J Neurosci. 2006 Mar 29;26(13):3404-11.
De Pietri Tonelli D, Mihailovich M, Di Cesare A, Codazzi F, Grohovaz F, Zacchetti D. Translational regulation of BACE-1 expression in neuronal and non-neuronal cells. Nucleic Acids Res. 2004 Mar 19;32(5):1808-17.
De Pietri Tonelli D, Mihailovich M, Schnurbus R, Pesole G, Grohovaz F, Zacchetti D. Translational control of Scamper expression via a cell-specific internal ribosome entry site. Nucleic Acids Res. 2003 May 15;31(10):2508-13.