Fondazione Santa Lucia IRCCS

Rome, Italy

Fondazione Santa Lucia IRCCS

Rome, Italy
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Valle C.,CNR Institute of Neuroscience | Carri M.T.,Fondazione Santa Lucia IRCCS | Carri M.T.,University of Rome Tor Vergata
Frontiers in Molecular Neuroscience | Year: 2017

Several proteins are found misfolded and aggregated in sporadic and genetic forms of amyotrophic lateral sclerosis (ALS). These include superoxide dismutase (SOD1), transactive response DNA-binding protein (TDP-43), fused in sarcoma/translocated in liposarcoma protein (FUS/TLS), p62, vasolin-containing protein (VCP), Ubiquilin-2 and dipeptide repeats produced by unconventional RAN-translation of the GGGGCC expansion in C9ORF72. Up to date, functional studies have not yet revealed a common mechanism for the formation of such diverse protein inclusions. Consolidated studies have demonstrated a fundamental role of cysteine residues in the aggregation process of SOD1 and TDP43, but disturbance of protein thiols homeostatic factors such as protein disulfide isomerases (PDI), glutathione, cysteine oxidation or palmitoylation might contribute to a general aberration of cysteine residues proteostasis in ALS. In this article we review the evidence that cysteine modifications may have a central role in many, if not all, forms of this disease. © 2017 Valle and Carrì.

Cozzolino M.,Fondazione Santa Lucia IRCCS | Cozzolino M.,CNR Institute of Neuroscience | Pesaresi M.G.,Fondazione Santa Lucia IRCCS | Pesaresi M.G.,University of Rome Tor Vergata | And 5 more authors.
Antioxidants and Redox Signaling | Year: 2012

Recent years have witnessed a renewed interest in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a late-onset progressive degeneration of motor neurons. The discovery of new genes associated with the familial form of the disease, along with a deeper insight into pathways already described for this disease, has led scientists to reconsider previous postulates. While protein misfolding, mitochondrial dysfunction, oxidative damage, defective axonal transport, and excitotoxicity have not been dismissed, they need to be re-examined as contributors to the onset or progression of ALS in the light of the current knowledge that the mutations of proteins involved in RNA processing, apparently unrelated to the previous old partners, are causative of the same phenotype. Thus, newly envisaged models and tools may offer unforeseen clues on the etiology of this disease and hopefully provide the key to treatment. © 2012 Mary Ann Liebert, Inc.

Dinuzzo M.,University of Rome La Sapienza | Mangia S.,University of Minnesota | Maraviglia B.,University of Rome La Sapienza | Giove F.,Fondazione Santa Lucia IRCCS | Giove F.,Museo Storico Della Fisica E Centro Of Studi E Ricerche Enrico Fermi
Journal of Cerebral Blood Flow and Metabolism | Year: 2010

In this paper, we combined several mathematical models of cerebral metabolism and nutrient transport to investigate the energetic significance of metabolite trafficking within the brain parenchyma during a 360-secs activation. Glycolytic and oxidative cellular metabolism were homogeneously modeled between neurons and astrocytes, and the stimulation-induced neuronal versus astrocytic Na inflow was set to 3:1. These assumptions resemble physiologic conditions and are supported by current literature. Simulations showed that glucose diffusion to the interstitium through basal lamina dominates the provision of the sugar to both neurons and astrocytes, whereas astrocytic endfeet transfer less than 4% of the total glucose supplied to the tissue. Neuronal access to paracellularly diffused glucose prevails even after halving (doubling) the ratio of neuronal versus astrocytic glycolytic (oxidative) metabolism, as well as after reducing the neuronal versus astrocytic Na+ inflow to a nonphysiologic value of 1:1. Noticeably, displaced glucose equivalents as intercellularly shuttled lactate account for ∼ 6% to 7% of total brain glucose uptake, an amount comparable with the concomitant drainage of the monocarboxylate by the bloodstream. Overall, our results suggest that the control of carbon recruitment for neurons and astrocytes is exerted at the level of glucose uptake rather than that of lactate shuttle. © 2010 ISCBFM All rights reserved.

Kohler S.,Maastricht University | Buntinx F.,Maastricht University | Buntinx F.,Catholic University of Leuven | Palmer K.,Fondazione Santa Lucia IRCCS | Van Den Akker M.,Maastricht University
Journal of the American Geriatrics Society | Year: 2015

Objectives To study the interaction between and timing effects of depression and vascular disorders on dementia risk. Design Retrospective cohort study. Setting Primary care practices in the south of the Netherlands. Participants Individuals in primary care aged 50 to 100 followed for 13 years (N = 35,791). Measurements Medical diagnoses of incident depression, hypertension, obesity, type 2 diabetes mellitus, stroke, and dementia were extracted from a research database. Cox proportional hazards regression was used to test whether incident depression predicted dementia and its putative interactions with vascular factors. Results In total, 1,680 participants developed dementia. Individuals with depression (n = 978) had a higher risk of dementia (adjusted hazard ratio (HR) = 2.03, 95% confidence interval (CI) = 1.56-2.64). Depression exerted most effect in participants with incident stroke (HR = 5.29, 95% CI = 2.52-11.14) or newly diagnosed hypertension (HR = 3.09, 95% CI = 1.54-6.20). Conclusion Depression in later life increases the risk of dementia. The effect is particularly high in individuals with depression and vascular disorders. Targeting late-onset depression in individuals with vascular disorders might lower dementia risk by preventing cerebrovascular changes. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

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.

Berretta N.,Fondazione Santa Lucia IRCCS | Bernardi G.,Fondazione Santa Lucia IRCCS | Bernardi G.,University of Rome Tor Vergata | Mercuri N.B.,Fondazione Santa Lucia IRCCS | Mercuri N.B.,University of Rome Tor Vergata
Journal of Physiology | Year: 2010

Dopamine (DA) neurones of the substantia nigra pars compacta (SNc) are involved in a wide variety of functions, including motor control and reward-based learning. In order to gain new insights into the firing properties of neuronal ensembles in the SNc, we recorded extracellular single units from spontaneously active neurones, using a multi-electrode array (MEA) device in midbrain slices. The majority of neurones (50.21%) had a low firing frequency (1-3 Hz) and a stable pacemaker-like pattern, while others (44.84%) were irregular, but still firing at a low rate. The remaining population (4.95%) comprised neurones with a regular higher firing rate (5-10 Hz). High rate neurones, on the whole, were insensitive to DA (30 μ m), while low rate neurones were mostly inhibited by DA, although responding either with a prominent or a weak inhibition. However, we recorded low rate regular neurones that were insensitive to DA, or irregular low rate neurones excited by DA. Interestingly, we found pairs of active neurones (12.10 ± 3.14%) with a significant proportion of spikes occurring synchronously. Moreover, the crosscorrelation probability in each pair tended to increase in response to DA. In conclusion, MEA recordings in midbrain slices reveal a much more complex picture than previously reported with regard to the firing pattern and DA sensitivity of spontaneously active SNc neurones. Moreover, the study opens new prospectives for the in vitro investigation of functional connectivity in the midbrain dopaminergic system, thus proposing new targets for the pharmacological treatment of DA-dependent neurological disorders. © 2010 The Authors. Journal compilation © 2010 The Physiological Society.

Lasaponara S.,University of Rome La Sapienza | Dragone A.,University of Rome La Sapienza | Lecce F.,Fondazione Santa Lucia IRCCS | Lecce F.,University College London | And 3 more authors.
Cortex | Year: 2015

To anticipate upcoming sensory events, the brain picks-up and exploits statistical regularities in the sensory environment. However, it is untested whether cumulated predictive knowledge about consciously seen stimuli improves the access to awareness of stimuli that usually go unseen. To explore this issue, we exploited the Attentional Blink (AB) effect, where conscious processing of a first visual target (T1) hinders detection of early following targets (T2). We report that timing uncertainty and low expectancy about the occurrence of consciously seen T2s presented outside the AB period, improve detection of early and otherwise often unseen T2s presented inside the AB. Recording of high-resolution Event Related Potentials (ERPs) and the study of their intracranial sources showed that the brain achieves this improvement by initially amplifying and extending the pre-conscious storage of T2s' traces signalled by the N2 wave originating in the extra-striate cortex. This enhancement in the N2 wave is followed by specific changes in the latency and amplitude of later components in the P3 wave (P3a and P3b), signalling access of the sensory trace to the network of parietal and frontal areas modulating conscious processing. These findings show that the interaction between conscious and unconscious processing changes adaptively as a function of the probabilistic properties of the sensory environment and that the combination of an active attentional state with loose probabilistic and temporal expectancies on forthcoming conscious events favors the emergence to awareness of otherwise unnoticed visual events. This likely provides an insight on the attentional conditions that predispose an active observer to unexpected "serendipitous" findings. © 2015 Elsevier Ltd.

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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