Laboratory of Pharmacology of Neurodegeneration
The main goal of the researches conducted in our laboratory is to study the molecular organization and the function of the glutamatergic excitatory synapse, both in physiological and pathological condition in order to identify new pharmacological targets for neurodegenerative disease as Parkinson Disease (PD) and Alzheimer Disease (AD).
The researches performed can be divided into:
- The study of structural organization of the glutamatergic excitatory synapse. The main aim is to study the composition of the post synaptic density with focus on NMDA receptor and its possible involvement in physiological process such as the synaptic plasticity.
The study of synaptonuclear messengers and identification of their physio-pathological role. The focus of this study is the characterization of Ring Finger Protein 10 (RNF10), its role in plasticity processes and learning and its involvement in AD.
- The study of NMDA receptor in PD and in L-DOPA-induced dyskinesias. The main focus of the study is to identify the role of the localization of specific subunits of NMDA receptor as a new pharmacological target for the treatment of PD and L-DOPA-induced dyskinesias.
- The study of ADAM10 in synaptic plasticity mechanisms and in AD. This study is focused on the analysis of the mechanisms able to modulate the localization of the enzyme at the post synaptic membrane and, therefore, its activity at the excitatory synapse.
In vitro Model
Rat and mouse hippocampal primary neurons, mouse cortical neurons , organotypic hippocampal slices, corticostriatal and hippocampal acute slices, cellular lines ( COS7, HEK293, CHO), fibroblasts.
In vivo Model
Animal Model of PD and L-DOPA induced dyskinesias, animal model of AD. Cognitive and motor behavioral test; stereotaxic surgery, osmotic pump implantation, dissection of cerebral areas and organs transplant.
Purification of subcellular fractions from neurons (microsomes, synaptosomes, post synaptic densities); trafficking, surface expression, internalization and deglycosilation assays; protein-protein interaction studies(pull down, immunoprecipitation).
Immunofluorescience, protein ligation assay, high resolution confocal microscopy, FRAP, trafficking and internalization assays.
Transient and stable trasfections, PCR, cloning, site specific mutagenesis, bacteria transformation, fusion proteins
National and International Collaborators
University of Bordeaux, France - Dr. Christophe Mulle, Dr. Erwan Bezard
University of Geneve, Switzerland – Dr.ssa Camilla Bellone
University of Heidelberg, Germany – Dr.ssa Daniela Mauceri
University of Newcastle, UK – Dr.ssa Claudia Racca
Philipps University of Marburg, Germany - Prof. Marco Rust
University of Napoli - Prof. Alessandro Usiello
University of Ancona – Prof. Daniele Di Marino
CNR – Milan - Dr. Carlo Sala, Dr. Chiara Verpelli
IRCCS Santa Lucia Roma - Dr. Barbara Picconi, Dr. Antonio Pisani
Mario Negri Milano Institute - Dr. Tiziana Borsello
University of Brescia - Prof. Alessandro Padovani, Prof.ssa Barbara Borroni
University of Cagliari - Dr. Manolo Carta
University of Novara - Prof. PierLuigi Canonico, Prof. Armando Genazzani
University of Perugia - Prof. Paolo Calabresi
University of Trento – Dr. Giovanni Piccoli
Mellone M, Zianni E, Stanic J, Campanelli F, Marino G, Ghiglieri V, Longhi A, Thiolat ML, Li Q, Calabresi P, Bezard E, Picconi B, Di Luca M, Gardoni F. NMDA receptor GluN2D subunit participates to levodopa-induced dyskinesia pathophysiology.Neurobiol Dis. 2019 Jan;121:338-349.
Alberio L, Locarno A, Saponaro A, Romano E, Bercier V, Albadri S, Simeoni F, Moleri S, Pelucchi S, Porro A, Marcello E, Barsotti N, Kukovetz K, Boender AJ, Contestabile A, Luo S, Moutal A, Ji Y, Romani G, Beltrame M, Del Bene F, Di Luca M, Khanna R, Colecraft HM, Pasqualetti M, Thiel G, Tonini R, Moroni A. A light-gated potassium channel for sustained neuronal inhibition. Nat Methods. 2018 Nov;15(11):969-976.
Dinamarca MC, Guzzetti F, Karpova A, Lim D, Mitro N, Musardo S, Mellone M, Marcello E, Stanic J, Samaddar T, Burguière A, Caldarelli A, Genazzani AA, Perroy J, Fagni L, Canonico PL, Kreutz MR, Gardoni F, Di Luca M. Ring finger protein 10 is a novel synaptonuclear messenger encoding activation of NMDA receptors in hippocampus. Elife. 2016 Mar 15;5:e12430.
Stanic J, Carta M, Eberini I, Pelucchi S, Marcello E, Genazzani AA, Racca C, Mulle C, Di Luca M, Gardoni F. Rabphilin 3A retains NMDA receptors at synaptic sites through interaction with GluN2A/PSD-95 complex. Nat Commun. 2015 Dec 18;6:10181.
Marcello E, Saraceno C, Musardo S, Vara H, de la Fuente AG, Pelucchi S, Di Marino D, Borroni B, Tramontano A, Pérez-Otaño I, Padovani A, Giustetto M, Gardoni F, Di Luca M. Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease. J Clin Invest. 2013 Jun;123(6):2523-38.