The development and the proper functionality of the central nervous system rely on a complex molecular and cellular machinery. Even minor alteration might have crucial impact on physiology and bring to disorders. We specially focus on Parkinson’s disease (PD) and autistic spectrum disorder (ASD) . PD is the second most common neurodegenerative disorder worldwide. To date, the most effective therapeutic approach to PD is based on the administration of L-DOPA which alleviate motor symptoms, but do not halt disease progression. ASD affects 0.9% of children. The mechanisms which lead to ASD are at best poorly understood. At the cellular level, it has been reported an abnormal organization of the cortical layer that may depend on abnormal cortical migration. There is urgent need to better understand the molecular mechanisms that lead to PD and ASD to design effective disease-modifying therapies. Our research aims at investigating the molecular bases of these diseases.
We use a multidisciplinary approach, ranging from in vitro functional assays to genetic animal models, to study the molecular bases of neurological disorders:
Presynaptic dysfunction in PD
Mutations in Lrrk2 gene represent the most common genetic cause of PD. LRRK2 encompasses several functional domains, including a kinase domain. Accumulating evidence describes LRRK2 kinase activity as the main trigger of PD. Our previous data demonstrate that LRRK2 is a key scaffolding protein at the presynaptic site, acting as a hub for protein-protein interaction. Cellular models of mutant LRRK2 show neurotransmission defects. We plan to identity and validate as therapeutic target LRRK2 substrates at the presynaptic site .
Migratory defects in ASD
ASD is characterized by neuronal-connectivity disruption. Mutations in the adhesion protein Negr1 have been identified in ASD-affected families. Negr1 is a GPI-anchored adhesion protein which expression is tightly modulated during neuron maturation. Our studies indicate that Negr1 acts as membrane bound molecule as well as soluble factor to regulate neuronal morphological maturation via RTK activation. We plan to characterize the pathway modulated by Negr1 in vitro and in vivo.
- Giovanni Piccoli, PI
- Caterina Montani, post-doc
- Maria Perez Carrion, post-doc
- Francesca Pischedda, post-doc
The Laboratory of Biology of Synapses has been established in 2015 through an agreement between CIBIO and the Fondazione Telethon.
- Elisa Greggio, Università di Padova, Padova, Italia
- Laura Cancedda, IIT , Genova, Italia
- Johannes Gloeckner, DZNE, Tubingen , Germany
- Franco Onofri, Università di Genova, Genova, Italia
- Michela Deleidi, DZNE, Tubingen, Germany
- Steven Condliffe, University of Otago, Otago, New Zealand
- Stefano Goldwurm, ICP-CTO, Milano, Italia
- The Dulbecco Telethon Laboratory of Biology of Synapses is part of TRAIN – “Trentino Autism Initiative”
Belluzzi E, Gonnelli A, Cirnaru MD, Marte A, Plotegher N, Russo I, Civiero L, Cogo S, Perèz Carrion M, Franchin C, Arrigoni G, Beltramini M, Bubacco L, Onofri F, Piccoli G, Greggio E. LRRK2 phosphorylates pre-synaptic N-ethylmaleimide sensitive fusion (NSF) protein enhancing its ATPase activity and SNARE complex disassembling rate. Mol Neurodegener MOND-D-15-00066R1
Pischedda F, Piccoli G. The IgLON family member Negr1 promotes neuronal arborization acting as soluble factor via FGFR2. Front. Mol. Neurosci. DOI: 10.3389/ fnmol.2015.00089
Civiero L, Cirnaru MD, Beilina A, Rodella U, Russo I, Belluzzi E, Lobbestael E, Reyniers L, Hondhamuni G, Lewis PA, Van den Haute C, Baekelandt V, Bandopadhyay R, Bubacco L, Piccoli G, Cookson MR, Taymans JM, Greggio E. LRRK2 interacts with PAK6 to control neurite complexity in mammalian brain. J Neurochem. 2015 Sep 16. doi: 10.1111/jnc.13369
Cirnaru MD, Marte A, Belluzzi E, Russo I, Gabrielli M, Longo F, Arcuri L, Murru L, Bubacco L, Matteoli M, Fedele E, Sala C, Passafaro M, Morari M, Greggio E, Onofri F and Piccoli G LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex Front. Mol. Neurosci. doi: 10.3389/fnmol.2014.00049
Pischedda F, Szczurkowska J, Cirnaru MD, Giesert F, Ueffing M, Sala C, Hauck S, Cancedda L and Piccoli G. A cell surface biotinylation assay to reveal membrane associated neuronal cues: Negr1 regulates neurites arborization Mol Cell Proteomics. 2014 Mar;13(3):733-48. doi: 10.1074/mcp.M113.031716
Piccoli G, Onofri F, Kastenmüller A, Cirnaru MD, Pischedda F, Marte A, Vogt A, Giesert F, Pan L, Antonucci F, Zhang M, Weinkauf S, Sala C, Matteoli M, Gloeckner CJ and Ueffing M Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain. Mol Cell Biol. 2014 Jun 15;34(12):2147-2161 doi: 10.1128/MCB.00914-13
Piccoli G, Condliffe B, Bauer M, Giesert F, Boldt K, Meixner A, Sarioglu H, Vogt-Weisenhorn DM, Wurst W, Gloeckner CJ, Matteoli M, Sala C, Ueffing M LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool. J Neurosci 2011 Feb 9;31(6):2225-37