0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
ABSTRACT OF THE TRANSNATIONAL COLLABORATIVE PROJECT
A novel concept has recently emerged in neurodegenerative disorders:
synaptic dysfunction may precede neuronal death by several years and can
underlie many important but still reversible symptoms. The present project is
a transnational and interdisciplinary study of the mechanisms that lead to
synaptic impairment and eventual demise of neurons in two prototypic neurodegenerative
conditions related to protein misfolding in which these
processes have been mostly studied, namely Alzheimer disease (AD) and
Huntington disease (HD). Both disorders involve production and deposition
of abnormal protein fragments which harm neurons.
The rationale of the proposed Era-Net Neuron collaboration is that some
cellular changes are shared by AD and HD, such as the dysregulation of Ca 2+
homeostasis and the mitochondrial function. The resulting Ca 2+ imbalance
will initially result in a “ synaptopathy ”, and eventually progress to the death
of neurons. At any given time, patients are likely to have cells at different
stages of this gradual pathologic process. Understanding the underlying
molecular mechanisms could lead to the identification of novel therapeutic
targets for intervention strategies in early stages of the pathology.
In a series of carefully designed and interactive sub-projects, we will use
different experimental approaches (molecular, cellular and animal models)
that exploit the diverse expertise available in the participating centers. We will
study synaptic dysfunction by imaging techniques in cell derived from transgenic
mice. We will monitor alterations of synaptic and dendritic spine
remodeling, investigate changes in receptor trafficking at the synapse, explore
disturbances in trafficking of different cellular components and study the role
of exosomes in neurodegeneration. We will place emphasis on the Ca 2+ -dependent
gene repressor DREAM.
Genes that are regulated by DREAM may control expression of proteins
that are important in both AD and HD. We have access to several lines of mice
that are genetically modified at different levels of DREAM-related signaling.
We will also pay special attention to the Permeability Transition Pore (PTP),
which is another important target of Ca 2+ /mitochondrial dysregulation that
may be affected in AD and HD. Changes in PTP can clearly cause a proapoptotic
situation of Ca 2+ -overload, and the PTP is thus a plausible drug target.
OVERALL AIMS OF THE CONSORTIUM, COORDINATION
AND MANAGEMENT
The proposal has two principal aims that are closely related. The first is
the fostering of collaboration among Laboratories in four European Countries
that work on a medically and socially important problem. However, the Consortium
will not only simply strive to create the critical mass without which
no significant advance will be possible. It will also integrate specific expertises
that are deemed essential to the success of the enterprise. This is the second
aim which was behind the decision to search for the types of know-how
whose integration would be the qualitative added value of the proposal.
610 2009