Fondazione Santa Lucia IRCCS

Rome, Italy

Fondazione Santa Lucia IRCCS

Rome, Italy
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Gerbino V.,Fondazione Santa Lucia IRCCS | Gerbino V.,University of Rome Tor Vergata | Carri M.T.,Fondazione Santa Lucia IRCCS | Carri M.T.,University of Rome Tor Vergata | And 3 more authors.
Neurobiology of Disease | Year: 2013

Genes encoding RNA-binding proteins have frequently been implicated in various motor neuron diseases, but the particular step in RNA metabolism that is vulnerable in motor neurons remains unknown. FUS, a nuclear protein, forms cytoplasmic aggregates in cells affected by amyotrophic lateral sclerosis (ALS), and mutations disturbing the nuclear import of FUS cause the disease. It is extremely likely that the cytoplasmic aggregates are cytotoxic because they trap important factors; the nature of these factors, however, remains to be elucidated. Here we show that FUS associates in a neuronal cell line with SMN, the causative factor in spinal muscular atrophy (SMA). The two genes work on the same pathway, as FUS binds to spliceosomal snRNPs downstream of the SMN function. Pathogenic FUS mutations do not disturb snRNP binding. Instead, cytoplasmic mislocalisation of FUS causes partial mis-localisation of snRNAs to the cytoplasm, which in turn causes a change in the behaviour of the alternative splicing machinery. FUS, and especially its mutations, thus have a similar effect as SMN1 deletion in SMA, suggesting that motor neurons could indeed be particularly sensitive to changes in alternative splicing. © 2013 Elsevier Inc.


Cozzolino M.,Fondazione Santa Lucia IRCCS | Carri M.T.,Fondazione Santa Lucia IRCCS | Carri M.T.,University of Rome Tor Vergata
Progress in Neurobiology | Year: 2012

In the present article, we review the many facets of mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease due to loss of upper motor neurons in cerebral cortex and lower motor neurons in brainstem and spinal cord. Accumulating evidence from recent studies suggests that the many, interconnected facets of mitochondrial dysfunction may play a more significant role in the etiopathogenesis of this disorder than previously thought. This notion stems from our expanding knowledge of the complex physiology of mitochondria and of alteration of their properties that might confer an intrinsic susceptibility to long-lived, post-mitotic motor neurons to energy deficit, calcium mishandling and oxidative stress.The wealth of evidence implicating mitochondrial dysfunction as a major event in the pathology of ALS has prompted new studies aimed to the development of new mitochondria-targeted therapies. However, it is now clear that drugs targeting more than one aspect of mitochondrial dysfunction are needed to fight this devastating disease. © 2011 Elsevier Ltd.


D'Ambrosi N.,Catholic University of the Sacred Heart | Rossi S.,National Research Council Italy | Gerbino V.,Fondazione Santa Lucia IRCCS | Gerbino V.,University of Rome Tor Vergata | Cozzolino M.,National Research Council Italy
Frontiers in Cellular Neuroscience | Year: 2014

Rac1 is a major player of the Rho family of small GTPases that controls multiple cell signaling pathways, such as the organization of cytoskeleton (including adhesion and motility), cell proliferation, apoptosis and activation of immune cells. In the nervous system, in particular, Rac1 GTPase plays a key regulatory function of both actin and microtubule cytoskeletal dynamics and thus it is central to axonal growth and stability, as well as dendrite and spine structural plasticity. Rac1 is also a crucial regulator of NADPH-dependent membrane oxidase (NOX), a prominent source of reactive oxygen species (ROS), thus having a central role in the inflammatory response and neurotoxicity mediated by microglia cells in the nervous system. As such, alterations in Rac1 activity might well be involved in the processes that give rise to Amyotrophic Lateral Sclerosis (ALS), a complex syndrome where cytoskeletal disturbances in motor neurons and redox alterations in the inflammatory compartment play pivotal and synergic roles in the final disease outcomes. Here we will discuss the genetic and mechanistic evidence indicating the relevance of Rac1 dysregulation in the pathogenesis of ALS. © 2014 Frontiers Research Foundation. All rights reserved.


Martorana A.,University of Rome Tor Vergata | Di Lorenzo F.,Fondazione Santa Lucia IRCCS | Esposito Z.,University of Rome Tor Vergata | Lo Giudice T.,University of Rome Tor Vergata | And 3 more authors.
Neuropharmacology | Year: 2013

Dopamine is a neurotransmitter involved in several brain functions ranging from emotions control, movement organization to memory formation. It is also involved in the regulation of mechanisms of synaptic plasticity. However, its role in Alzheimer's disease (AD) pathogenesis is still puzzling. Several recent line of research instead indicates a clear role for dopamine in both amyloid β formation as well as in cognitive decline progression. In particular it has been shown that dopamine D2-like receptors (namely D3 and D2) could be mostly responsible for dopamine dysfunction in AD. Here we aimed to study the effects of the dopamine agonist Rotigotine on cortical excitability and on central cholinergic transmission in cases of AD. Rotigotine is a dopamine agonist with a pharmacological profile with high affinity for D3 and D2 receptors. We used paired pulse protocols assessing short intracortical inhibition (SICI) and intracortical facilitation (ICF) to asses cortical excitability over the primary motor cortex and Short Latency Afferent Inhibition (SLAI) protocols, to verify the effects of the drug on central cholinergic transmission in a group of AD patients compared to age-matched controls. We observed that rotigotine induces unexpected changes in both cortical excitability (increased) and central cholinergic transmission (restored) of AD patients. These unexpected effects might depend on the dopamine D2-like receptors dysfunction previously described in AD brains. The current findings could indicate that future strategies aimed to ameliorate symptoms of the related AD cognitive decline could also involve some dopaminergic drugs. This article is part of a Special Issue entitled 'Cognitive Enhancers'. © 2012 Elsevier Ltd. All rights reserved.


Gardoni F.,University of Milan | Ghiglieri V.,Fondazione Santa Lucia IRCCS | Luca M.D.,University of Milan | Calabresi P.,University of Perugia
Progress in Brain Research | Year: 2010

N-methyl-. d-aspartate (NMDA) receptors have been implicated as a mediator of neuronal injury associated with many neurological disorders including ischemia, epilepsy, brain trauma, dementia and neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease. To this, non-selective NMDA receptor antagonists have been tried and have been shown to be effective in many experimental animal models of disease, and some of these compounds have moved into clinical trials. However, the initial enthusiasm for this approach has waned, because the therapeutic index for most NMDA antagonists is quite poor, with significant adverse effects at clinically effective doses, thus limiting their utility. More recently, the concept that the exact pathways downstream NMDA receptor activation could represent a key variable element among neurological disorders has been put forward. In particular, variations in NMDA receptor subunit composition could be important in different disorders, both in the pathophysiological mechanisms of cell death and in the application of specific symptomatic therapies. As to PD, NMDA receptor complex has been shown to be altered in experimental models of parkinsonism and in PD in humans. Further, it has become increasingly evident that the NMDA receptor complex is intimately involved in the regulation of corticostriatal long-term potentiation, which is altered in experimental parkinsonism. The following sections will examine the modifications of specific NMDA receptor subunits as well as post-synaptic associated signalling complex including kinases and scaffolding proteins in experimental parkinsonism. These findings may allow the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for PD. © 2010 Elsevier B.V.


Ghiglieri V.,Fondazione Santa Lucia IRCCS | Sgobio C.,Fondazione Santa Lucia IRCCS | Costa C.,University of Perugia | Picconi B.,Fondazione Santa Lucia IRCCS | And 2 more authors.
Progress in Neurobiology | Year: 2011

In neurological disorders in which the cross-talk between striatal and hippocampal memory systems is affected, such as epilepsy, Down syndrome and Huntington's disease, cell-type specific alterations in synaptic plasticity lead to distinctive patterns causing functional imbalance between the two memory systems. Despite the complex network in which their neuronal activity is likely to be engaged, a common property of striatal and hippocampal neurons is to undergo bidirectional synaptic plasticity that relies on activity of interneurons and correlates with specific learning skills. As interneuronal dysfunction plays a primary role in the pathogenesis of these disorders, interneurons can be viewed as critical elements in neurophysiological substrates of such flexible relationships between these two memory systems. © 2011 Elsevier Ltd.


Achsel T.,Catholic University of Leuven | Barabino S.,University of Milan Bicocca | Cozzolino M.,CNR Institute of Neuroscience | Carr M.T.,Fondazione Santa Lucia IRCCS | Carr M.T.,University of Rome Tor Vergata
Biochemical Society Transactions | Year: 2013

MNDs (motor neuron diseases) form a heterogeneous group of pathologies characterized by the progressivedegeneration of motor neurons. More and more genetic factors associated with MND encode proteinsthat have a function in RNA metabolism, suggesting that disturbed RNA metabolism could be a commonunderlying problem in several, perhaps all, forms of MND. In the present paper we review recentdevelopments showing a functional link between SMN (survival of motor neuron), the causative factorof SMA (spinal muscular atrophy), and FUS (fused in sarcoma), a genetic factor in ALS (amyotrophic lateralsclerosis). SMN is long known to have a crucial role in the biogenesis and localization of the spliceosomalsnRNPs (small nuclear ribonucleoproteins), which are essential assembly modules of the splicing machinery.Now we know that FUS interacts with SMN and pathogenic FUS mutations have a significant effect on snRNPlocalization. Together with other recently published evidence, this finding potentially links ALS pathogenesisto disturbances in the splicing machinery, and implies that pre-mRNA splicing may be the common weakpoint in MND, although other steps in mRNA metabolism could also play a role. Certainly, further comparisonof the RNA metabolism in different MND will greatly help our understanding of the molecular causes ofthese devastating diseases. © 2013 Biochemical Society.


Binetti N.,Fondazione Santa Lucia IRCCS
Journal of vision | Year: 2012

Several studies show that visual stimuli traveling at higher velocities are overestimated with respect to slower, or stationary, stimuli of equivalent physical duration. This effect-time dilation-relates more in general to several accounts highlighting a quantitative relationship between the amount of changes a stimulus is subject to and the perceived duration: faster stimuli, subject to a greater number of changes in space, lead to overestimated durations of displacement. In the present paper we provide evidence of a new illusory effect, in which the apparent duration of a sensory event is affected by the way a constant number of changes are delivered in time, or in time and space. Participants judged accelerating and decelerating sequences of stationary flickering stimuli (Experiments 1 and 3) and accelerating and decelerating horizontally drifting visual stimuli (Experiment 2) on the fronto-parallel plane. Acceleration and deceleration were achieved by irregular sequencing of events in time (anisochronous flicker rate) or irregular sequencing of events in time and space (anisochronous and/or anisometric drift). Despite being characterized by the same amounts of visual changes, accelerating and decelerating sequences lead to opposite duration biases (underestimation and overestimation errors, respectively). We refer to this effect in terms of ATI: Aniso-Time-Illusion. This bias was observed in both subsecond (760 ms) and suprasecond ranges (1900 ms). These data highlight how the spatio-temporal evolution of dynamic visual events, asides the overall quantity of changes they are subject to, affect the perceived amount of time they require to unfold.


Cozzolino M.,CNR Institute of Neuroscience | Ferri A.,Fondazione Santa Lucia IRCCS | Ferri A.,CNR Institute of Neuroscience | Valle C.,Fondazione Santa Lucia IRCCS | And 3 more authors.
Molecular and Cellular Neuroscience | Year: 2013

Evidence from patients with sporadic and familiar amyotrophic lateral sclerosis (ALS) and from models based on the overexpression of mutant SOD1 found in a small subset of patients, clearly point to mitochondrial damage as a relevant facet of this neurodegenerative condition. In this mini-review we provide a brief update on the subject in the light of newly discovered genes (such as TDP-43 and FUS/TLS) associated to familial ALS and of a deeper knowledge of the mechanisms of derangement of mitochondria. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'. © 2012 Elsevier Inc.


Carri M.T.,Fondazione Santa Lucia IRCCS | Carri M.T.,University of Rome Tor Vergata | Cozzolino M.,Fondazione Santa Lucia IRCCS
Journal of Bioenergetics and Biomembranes | Year: 2011

Mutant Cu,Zn superoxide dismutase (mutSOD1) is found in a subset of patients with familial amyotrophic lateral sclerosis (ALS), a fatal progressive paralysis due to loss of motor neurons. In the present article, we review existing evidence linking the expression of mutSOD1 to the many facets of mitochondrial dysfunction in ALS, with a focus on recent studies suggesting that the association and misfolding of the mutant protein (and possibly of the wild type protein as well) within these organelles is causally linked to their functional and structural alterations. Energy deficit, calcium mishandling and oxidative stress are paralleled by alteration in mitochondrial motility, dynamics and turnover and most probably lead to mitochondriadependent cell death. Thus, the development of new, selective mitochondria-targeted therapies may constitute a promising approach in the treatment of SOD1-linked ALS. © 2011 Springer Science+Business Media, LLC.

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