Research Group

Fossati Group

Cell Biology of the Synapse Lab

Fossati Group

Matteo Fossati

Junior Group Leader

Our lab investigates the cellular and molecular mechanisms underlying synapse development in vivo, with the final goal of understanding the molecular logistics of brain development and how these processes are dysregulated in neurodevelopmental disorders.

The challenge

Synapses are the elementary functional units of the brain ensuring information processing and storage in the brain. Their proper assembly and maturation are crucial to generate fully functional neuronal circuits. Indeed, impairments of these processes are thought to determine a wide spectrum of neurodevelopmental and psychiatric disorders, collectively called synaptopathies, such as autism, epilepsy and schizophrenia. In particular, the fine orchestration of excitatory and inhibitory synaptogenesis is fundamental to set a balanced ratio between excitation and inhibition in the brain, a key parameter for correct brain development and function. However, our understanding of the molecular pathways that govern synaptogenesis and that are affected in pathological conditions is still very limited. To this aim, we exploit an interdisciplinary approach that integrates a range of in vivo molecular tools with advanced imaging (including super-resolution microscopy), proteomics and biochemistry.

Main research areas

Pathogenic mechanisms of the Angelman syndrome and autism

We study two neurodevelopmental disorders that are caused by defects of the UBE3A gene. The loss of UBE3A leads to the Angelman Syndrome (AS), a severe brain disease characterized by severe intellectual deficit, motor dysfunction, unusually happy demeanor, seizures and sleep disorder, while duplications or triplications of UBE3A are the most common cytogenetic alterations in autism. UBE3A encodes the E3 ubiquitin ligase E3A, which has dual functions acting as E3 ubiquitin ligase and transcriptional co-activator. Although data from AS models suggest that UBE3A plays a key role in modulating synaptic pathways important for cognition and behavior, the precise mechanisms of UBE3A function and its critical substrates remain elusive. Here, we propose to molecularly dissect the mechanism underlying the function of the AS- and autism-associated UBE3A gene in synaptic development. Hence, we anticipate that this research program might uncover novel pathogenic insights into the development of AS and autism and hopefully offer new therapeutic perspectives to treat these as yet incurable diseases.

Role of the early secretory pathway in synapse development and function

Neurons face the daunting task of regulating the repertoire of their surface proteome to its site of action, at the right time and in the right amount within their immense and complex morphology. This is even more challenging at synapses. Given the great level of molecular diversity and their plastic nature, sophisticated trafficking mechanisms are required to ensure proper synaptic development and function. Yet, how neurons accomplish this taxing challenge is unclear. In particular, the role of the early secretory pathway, which represents the entry point and the first rate-limiting step of protein delivery to synaptic membrane is largely unexplored. In this research program we take an interdisciplinary approach to answer this fundamental question in neurobiology. Given that several brain disorders display impaired trafficking, this project might also provide a means to manipulate intracellular trafficking and, hopefully, offer new therapeutic perspectives to correct these defects.

Dissecting the role of the KLHL17 gene in the molecular pathogenesis of the West syndrome

Developmental and epileptic encephalopathies (DEE) refer to a group of infantile epilepsies that affect millions of people worldwide and represent a major socio-economic burden. This project focuses on a specific DEE, the West syndrome (WS, also referred to as infantile spasms), which has a multifactorial etiology, and the underlying pathogenic mechanisms are largely unknown. Among the WS-risk genes, KLHL17 was found associated in a cohort of patients. In this project we propose to interrogate the molecular function of KLHL17 and its protein interaction network in vivo. Thus, this project might unveil the role of KLHL17 gene in the assembly and maturation of neuronal circuits, and provide the rationale to develop reasoned therapeutic approaches to mitigate WS clinical manifestations.

Selected publications

Iannielli A
Cell Death Dis
Modeling native and seeded Synuclein aggregation and related cellular dysfunctions in dopaminergic neurons derived by a new set of isogenic iPSC lines with SNCA multiplications.
Gemin O
PLoS Biol
Unique properties of dually innervated dendritic spines in pyramidal neurons of the somatosensory cortex uncovered by 3D correlative light and electron microscopy.
Fossati M
Curr Opin Neurobiol
Trans-synaptic interactions of ionotropic glutamate receptors.
Folci A
Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium between Synapse Physiology and Intellectual Disability.
Fossati M
Trans-Synaptic Signaling through the Glutamate Receptor Delta-1 Mediates Inhibitory Synapse Formation in Cortical Pyramidal Neurons.
Zapata J
Nat Commun
Epilepsy and intellectual disability linked protein Shrm4 interaction with GABA(B)Rs shapes inhibitory neurotransmission.
Fossati M
SRGAP2 and Its Human-Specific Paralog Co-Regulate the Development of Excitatory and Inhibitory Synapses.
Fossati M
A positive signal prevents secretory membrane cargo from recycling between the Golgi and the ER.
Fossati M
Cell Logist
An investigation of the effect of membrane curvature on transmembrane-domain dependent protein sorting in lipid bilayers.
Fossati M
J Vis Exp
Visualization of endoplasmic reticulum subdomains in cultured cells.
Cappello V
Mol Cell Neurosci
Analysis of neuromuscular junctions and effects of anabolic steroid administration in the SOD1G93A mouse model of ALS.
Papiani G
J Cell Sci
Restructured endoplasmic reticulum generated by mutant amyotrophic lateral sclerosis-linked VAPB is cleared by the proteasome.
Costantini LM
Assessing the tendency of fluorescent proteins to oligomerize under physiologic conditions.
Assessing the Nanoscale Organization of Excitatory and Inhibitory Synapses Using Recombinant Probes to Visualize Endogenous Synaptic Proteins

Group members

Fossati Group
Federica Baronchelli

PhD Student

Fossati Group
Martina Biagioni

Postdoc Fellow

Fossati Group
Matteo Fossati

Junior Group Leader

Fossati Group
Ibrahim Raya

PhD Student