Mapping of Italian research excellence in Neurodegenerative - Apre

Nome Flavia Valtorta
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Flavia Valtorta, Fabio Grohovaz, Daniele Zacchetti
02-2643-4826 (Valtorta) 4811 (Grohovaz), 4817 (Zacchetti)
valtorta.flavia@hsr.it, grohovaz.fabio@hsr.it, zacchetti.daniele@hsr.it
Istituto/Dipartimento San Raffaele Scientific Institute, Division of Neuroscience
Via Olgettina 58
20132 Milano, ITALT
Proposta di ricerca.
Molecular mechanisms in neurotrasmission: effects of neuron and glia phenotypes in synaptic efficiency and
synaptopathy
Comprehensive goal of our research is the elucidation of the molecular mechanisms that underlie communications
between cells of the brain, both in the adult and during development. This proposal involves the complementary
expertise and the tight collaboration of two research units: the NEUROPSYCHOPHARMACOLOGY UNIT (Flavia
Valtorta) and the CELLULAR NEUROPHYSIOLOGY UNIT (Fabio Grohovaz and Daniele Zacchetti).
The main form of communication between neurons is achieved at the synaptic level through regulated secretion of
neurotransmitter. This process is of paramount importance for information processing in the central nervous system
and is known to undergo dysfunction in a number of pathophysiological states. Substantial advancements have been
made concerning the identification of the proteins involved in the basic mechanism of neurotransmitter release.
Much less is known about the molecules that participate to the assembly of the complex synaptic machinery during
development.
Research in Valtorta’s group will develop along two main lines: Aim 1: Diseases of synaptic origin. The main focus will
be on the family of the synapsins and their link to epilepsy and autism. Synapsins are a family of brain
phosphoproteins involved in neurotransmitter release through regulation of synaptic vesicle availability. Recent data
from the lab show that synapsins have also an important function in the organization of synaptic contacts. Synapsin
KO mice develop an epileptic phenotype, and mutations in the human synapsin genes have been recently associated
with epilepsy and autism spectrum disorders. The central interest is to investigate the molecular roles of synapsin in
synapse formation and function, and how these roles relate to the development of brain pathology. Another project
concerns the identification of novel molecular interactors of synuclein and of their role in neurodegeneration
associated with Parkinson disease.
Aim 2: Membrane trafficking in neuronal development. The process that leads from undifferentiated, round neuronal
precursors to fully differentiated, highly polarized neurons is extremely complex. Among the various phenomena
driving this process, those associated with membrane trafficking are of fundamental importance. The group is
interested in studying membrane trafficking in the very early steps of neuronal development. In this respect, they
have identified a process of developmentally-regulated, high-capacity endocytosis as one of the earliest marker of
neuronal polarity, and will investigate its function in neuronal commitment and axon pathfinding. This investigation
will be extended to the phenotypical characterization of the early steps of neuronal commitment of neural
stem/progenitor cells and iPS (induced-pluripotent stem cells). In the same cells, the late steps of neuronal
development will also be studied, i.e. the formation of synapses and their functional refinement, which are essential
phenomena for the proper integration of cells in neuronal networks.
The work in Grohovaz’s research unit is focused on the general comprehension of the physiopathological
mechanisms underlying neuroprotection or leading to neurodegeneration. The group mostly uses brain primary
cultures and applys molecular biology and in vitro cellular approaches, including live cell imaging (calcium imaging
and total internal reflection microscopy). Electrophysiology and animal behavioral studies are conducted in
collaboration with other research groups.
A main project deals with the generation of oxidative stress and the ensuing protection mechanisms in both neurons
and astrocytes. In particular, the mechanisms of iron entry and its influence on the production of reactive oxygen
species are investigated. On the other hand, in light of the importance of neuroinflammation, interest is also directed
to the role of glia in the neurodegenerative processes. More specifically, the molecular mechanisms involved in the
process of glia activation and the influence the activated phenotype has on neuronal survival are investigated.
Along with the study of these general physiopathological mechanisms, the group addresses specific issues within the
following disease-oriented projects:
(i) Alzheimer’s disease pathogenesis: the regulation of BACE1/BACE2 expression; the implication of beta-secretase
activity on amyloid-beta deposition; the cellular effects of the various amyloid-beta forms on different cell types from
brain.
(ii) Derangement in intracellular iron homeostasis and hereditary ferritinopathy: analysis of the mechanisms of iron