The research carried out in this laboratory is aimed at characterizing the post-transcriptional molecular mechanisms underlying the polarized expression of messenger RNA (mRNA) in neurons. We are also interested in understanding if alterations of such mechanisms contribute to the development of neurological disorders, such as Alzheimer’s.

In particular, the laboratory carries out two lines of research:

1. Post-transcriptional regulation of Arc mRNA in synaptic plasticity and in Alzheimer’s Disease

Post-transcriptional gene regulation is particularly important for the correct maturation and activity of neurons, polarized cells which respond to external stimuli via the timely expression of localized proteins in peripheral subcellular domains. In this laboratory, we have characterized a particular regulatory mechanism that finely controls the levels of Arc protein, an important sensor and effector of essential synaptic plasticity and memory consolidation. This mechanism depends on splicing of Arc’s introns, uniquely positioned in the 3 ‘untranslated region (UTR) of its mRNA; in response to synaptic stimulation, splicing of these introns modulates both stability and translational efficiency of Arc mRNA, allowing for a transient and activity-dependent expression of Arc protein. Since it has been shown that alterations in Arc levels can lead to the accumulation of beta amyloid protein and contribute to memory deficits associated with Alzheimer’s Disease, we are interested in understanding whether an altered post-transcriptional regulation of Arc mRNA is involved in the development of this neurodegenerative disease. In particular, we are analyzing Single Nucleotide Polymorphisms (SNPs) present in Arc’s 3 UTR  that alter the susceptibility to developing the disease, in order to understand its molecular mechanism. Furthermore, we have started to study the post-transcriptional regulation of genes that are key to inhibitory GABAergic neurons, a neuronal class which modulates neuronal excitability and rhytmogenesis, and whose dysfunction leads to numerous disorders including epilepsy. 2.      Post-transcriptional regulation of the p75NTR neurotrophin receptor Another line of research of the laboratory focuses on the post-transcriptional regulation of the neurotrophin p75^NTR receptor which, among its many functions, contributes to specifying axonal polarity during neuronal differentiation. Although this receptor has been thoroughly studied at the protein level, very little is known about the mechanisms that regulate gene expression at the post-transcriptional level, particularly during neuronal maturation. Using cultures of primary neurons and molecular biology approaches, we have discovered a non-coding antisense RNA that modulates p75^NTR expression levels and participates in the axon specification process.

Selected Publications

Giorgi C, Yeo GW, Stone ME, Katz DB, Burge C, Turrigiano G, Moore MJ. The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression. Cell 2007 July 13:179-91. PubMed Full text

Paolantoni C, Ricciardi S, De Paolis V, Okenwa C, Catalanotto C, Ciotti MT, Cattaneo A, Cogoni C, Giorgi C. Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling. Front Mol Neurosci. 2018 Apr 27;11:145. PubMed Full text

Marangon D, Boda E, Parolisi R, Negri C, Giorgi C, Montarolo F, Perga S, Bertolotto A, Buffo A, Abbracchio MP, Lecca D. In vivo silencing of miR-125a-3p promotes myelin repair in models of white matter demyelination.  Glia. 2020 Mar12. PubMed Full Text