Vincenzo Silani

Publications (73)358.17 Total impact

• Source

  Available from: Viviana Pensato

  Dataset: UBQLN2

  Pamela Milani, Antonia Ratti, Roberto Del Bo, Annachiara Cagnin, Lucia Corrado, Sandra D'Alfonso, Barbara Castellotti, Cinzia Tiloca, Viviana Pensato, Jennifer Agostini, [......], Giacomo Pietro Comi, Giulietta Riboldi, Cristina Cereda, Nicola Ticozzi, Letizia Mazzini, Vincenzo Silani, Cinzia Gellera, Gianni Sorarù, Stefania Corti, Alessandra Bagarotti
• Article: Pilot trial of clenbuterol in spinal and bulbar muscular atrophy.

  Giorgia Querin, Carla D'Ascenzo, Enrico Peterle, Mario Ermani, Luca Bello, Paola Melacini, Lucia Morandi, Letizia Mazzini, Vincenzo Silani, Monika Raimondi, Jessica Mandrioli, Silvia Romito, Corrado Angelini, Elena Pegoraro, Gianni Sorarù
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  ABSTRACT: OBJECTIVE: To test the efficacy and tolerability of clenbuterol in patients with spinal and bulbar muscular atrophy (SBMA). METHODS: Twenty patients with a diagnosis of SBMA were given oral clenbuterol (0.04 mg/d) for 12 months. The primary efficacy end point was the change from baseline of the walking distance covered in 6 minutes at 12 months. Secondary end points included the change over time in muscle strength assessed with the Medical Research Council scale, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and forced vital capacity values. Safety was assessed by a series of laboratory and instrumental tests, as well as reporting of adverse events. RESULTS: Sixteen patients completed the study. There was a significant and sustained increase in walking distance covered in 6 minutes and forced vital capacity between the baseline and the 12-month assessments (p < 0.001). No differences were recorded in Medical Research Council or ALSFRS-R scores between baseline and follow-up assessments. Serious side effects, including those on heart function, were absent. A significant increase in serum creatine kinase levels was observed. CONCLUSIONS: Our findings suggest a positive effect of clenbuterol on SBMA disease progression. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that clenbuterol is effective in improving motor function in SBMA.
  Neurology 05/2013; · 8.31 Impact Factor
• Article: Intrahemispheric and interhemispheric structural network abnormalities in PLS and ALS.

  Federica Agosta, Sebastiano Galantucci, Nilo Riva, Adriano Chiò, Stefano Messina, Sandro Iannaccone, Andrea Calvo, Vincenzo Silani, Massimiliano Copetti, Andrea Falini, Giancarlo Comi, Massimo Filippi
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  ABSTRACT: Using diffusion tensor (DT) magnetic resonance imaging (MRI), damage to brain intrahemispheric and interhemispheric connections was assessed in 26 sporadic primary lateral sclerosis (PLS) patients compared with 28 sporadic amyotrophic lateral sclerosis (ALS) patients with similar disability and 35 healthy controls. DT MRI diagnostic accuracy in distinguishing the two motor neuron disease (MND) variants was tested. PLS and ALS patients showed a distributed pattern of abnormalities of the motor system, including the corticospinal tracts and corpus callosum (CC). PLS versus ALS patients showed a more severe damage to the motor CC fibers and subcortical white matter (WM) underlying the primary motor cortices. Both patient groups showed an extra-motor damage, which was more severe in PLS. This did not appear to be driven by longer disease duration in PLS. In PLS patients, damage to the CC mid-body correlated with the severity of upper motor neuron clinical burden. CC fractional anisotropy values had the highest accuracy in distinguishing PLS from controls and ALS. PLS and ALS share an overlapped pattern of WM abnormalities. This underscores that PLS, despite its distinct clinical phenotype and long survival, still lies within the wider MND spectrum. Whether CC diffusivity may be a novel marker to increase confidence in an early diagnostic separation of PLS from ALS still needs to be investigated. Hum Brain Mapp, 2013. © 2013 Wiley-Periodicals, Inc.
  Human Brain Mapping 04/2013; · 5.88 Impact Factor
• Article: ELAV proteins along evolution: Back to the nucleus?

  Claudia Colombrita, Vincenzo Silani, Antonia Ratti
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  ABSTRACT: The complex interplay of post-transcriptional regulatory mechanisms mediated by RNA-binding proteins (RBP) at different steps of RNA metabolism is pivotal for the development of the nervous system and the maintenance of adult brain activities. In this review, we will focus on the highly conserved ELAV gene family encoding for neuronal-specific RBPs which are necessary for proper neuronal differentiation and important for synaptic plasticity process. In the evolution from Drosophila to man, ELAV proteins seem to have changed their biological functions in relation to their different subcellular localization. While in Drosophila, they are localized in the nuclear compartment of neuronal cells and regulate splicing and polyadenylation, in mammals, the neuronal ELAV proteins are mainly present in the cytoplasm where they participate in regulating mRNA target stability, translation and transport into neurites. However, recent data indicate that the mammalian ELAV RBPs also have nuclear activities, similarly to their fly counterpart, enabling them to continuously shuttle between the cytoplasm and the nucleus. Here, we will review and comment on all the biological functions associated with neuronal ELAV proteins along evolution and will show that the post-transcriptional regulatory network mediated by these RBPs in the brain is highly complex and only at an initial stage of being fully understood. This article is part of a Special Issue entitled 'RNA and splicing regulation in neurodegeneration'.
  Molecular and Cellular Neuroscience 02/2013; · 3.66 Impact Factor
• Article: Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS.

  Ettore Beghi, Elisabetta Pupillo, Virginio Bonito, Paolo Buzzi, Claudia Caponnetto, Adriano Chiò, Massimo Corbo, Fabio Giannini, Maurizio Inghilleri, Vincenzo La Bella, [......], Lorenzo Lorusso, Christian Lunetta, Letizia Mazzini, Paolo Messina, Gabriele Mora, Michele Perini, Maria Lidia Quadrelli, Vincenzo Silani, Isabella L Simone, Lucio Tremolizzo
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  ABSTRACT: Our objective was to assess the effects of acetyl-L-carnitine (ALC) with riluzole on disability and mortality of amyotrophic lateral sclerosis (ALS). Definite/probable ALS patients, 40-70 years of age, duration 6-24 months, self-sufficient (i.e. able to swallow, cut food/handle utensils, and walk), and with forced vital capacity (FVC) > 80% entered a pilot double-blind, placebo-controlled, parallel group trial and were followed for 48 weeks. ALC or placebo 3 g/day was added to riluzole 100 mg/day. Primary endpoint: number of patients no longer self-sufficient. Secondary endpoints: changes in ALSFRS-R, MRC, FVC and McGill Quality of Life (QoL) scores. Analysis was made in the intention-to-treat (ITT) and per-protocol (PP) population, completers and completers/compliers (i.e. taking > 75% of study drug). Forty-two patients received ALC and 40 placebo. In the ITT population, 34 (80.9%) patients receiving ALC and 39 (97.5%) receiving placebo became non-self-sufficient (p = 0.0296). In the PP analysis, percentages were 84.4 and 100.0% (p = 0.0538), respectively. Mean ALSFRS-R scores at 48 weeks were 33.6 (SD 10.4) and 27.6 (9.9) (p = 0.0388), respectively, and mean FVC scores 90.3 (32.6) and 58.6 (31.2) (p = 0.0158), respectively. Median survival was 45 months (ALC) and 22 months (placebo) (p = 0.0176). MRC, QoL and adverse events were similar. In conclusion, ALC may be effective, well-tolerated and safe in ALS. A pivotal phase III trial is needed.
  Amyotrophic lateral sclerosis and frontotemporal degeneration. 02/2013;
• Article: Charles Bonnet syndrome: two case reports and review of the literature.

  Alberto Lerario, Andrea Ciammola, Barbara Poletti, Floriano Girotti, Vincenzo Silani
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  ABSTRACT: Visual hallucinations (VHs) can be associated with a variety of clinical conditions, and are also experienced by healthy people due to visual impairment. The condition is known as Charles Bonnet Syndrome (CBS). The circumstances favoring VHs support the hypothesis that sensory deprivation enhances the ongoing activity of the visual system after sensory loss. Clinician should be aware that a significant proportion of visually impaired patients experience complex VHs, which are sometimes distressing. Herein, we report two cases of CBS. Case 1 is a 60-year-old man with visual impairment due to orbit pseudotumor in autoimmune hypothyroidism. Case 2 is an 87-year-old woman with Parkinson's disease and a 15-year history of intermittent complex VHs due to age-related macular degeneration in both eyes. In both cases investigations for alternative pathological causes of VHs were negative and, therefore, the aetiology of hallucinations was attributed to CBS. The course and treatment of CBS patients vary according to the nature of the visual dysfunction. Drug treatments remain partially satisfactory, with individual cases successfully treated with atypical antipsychotics. Nonpharmacological interventions aimed to reduce the visual pathway deprivation. Reassurance of the benign nature of CBS is essential to support patients and reduce caregiver's burden.
  Journal of Neurology 02/2013; · 3.47 Impact Factor
• Source

  Available from: Cristina Cereda

  Article: Ubiquilin 2 mutations in Italian patients with amyotrophic lateral sclerosis and frontotemporal dementia.

  Cinzia Gellera, Cinzia Tiloca, Roberto Del Bo, Lucia Corrado, Viviana Pensato, Jennifer Agostini, Cristina Cereda, Antonia Ratti, Barbara Castellotti, Stefania Corti, [......], Pamela Milani, Carlo Gabelli, Giulietta Riboldi, Letizia Mazzini, Gianni Sorarù, Sandra D'Alfonso, Franco Taroni, Giacomo Pietro Comi, Nicola Ticozzi, Vincenzo Silani
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  ABSTRACT: OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly involving cortical and spinal motor neurones. Molecular studies have recently identified different mutations in the ubiquilin-2 (UBQLN2) gene as causative of a familial form of X-linked ALS, 90% penetrant in women. The aim of our study was to analyse the UBQLN2 gene in a large cohort of patients with familial (FALS) and sporadic (SALS) amyotrophic lateral sclerosis, with or without frontotemporal dementia (FTD), and in patients with FTD. METHODS: We analysed the UBQLN2 gene in 819 SALS cases, 226 FALS cases, 53 ALS-FTD patients, and 63 patients with a clinical record of FTD. Molecular analysis of the entire coding sequence was carried out in all FALS and ALS-FTD patients, while SALS and FTD patients were analysed specifically for the genomic region coding for the PXX repeat tract. Healthy controls were 845 anonymous blood donors and were screened for the PXX repeat region only. RESULTS: We found five different variants in the UBQLN2 gene in five unrelated ALS patients. Three variants, including two novel ones, involved a proline residue in the PXX repeat region and were found in three FALS cases. The other two were novel variants, identified in one FALS and one SALS patient. None of these variants was present in controls, while one control carried a new heterozygous variant. CONCLUSIONS: Our data support the role of the UBQLN2 gene in the pathogenesis of FALS, being conversely a rare genetic cause in SALS even when complicated by FTD.
  Journal of neurology, neurosurgery, and psychiatry 11/2012; · 4.87 Impact Factor
• Article: Screening of the PFN1 gene in sporadic amyotrophic lateral sclerosis and in frontotemporal dementia.

  Cinzia Tiloca, Nicola Ticozzi, Viviana Pensato, Lucia Corrado, Roberto Del Bo, Cinzia Bertolin, Chiara Fenoglio, Stella Gagliardi, Daniela Calini, Giuseppe Lauria, [......], Letizia Mazzini, Cristina Cereda, Elio Scarpini, Gianni Sorarù, Giacomo P Comi, Sandra D'Alfonso, Cinzia Gellera, Antonia Ratti, John E Landers, Vincenzo Silani
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  ABSTRACT: Mutations in the profilin 1 (PFN1) gene, encoding a protein regulating filamentous actin growth through its binding to monomeric G-actin, have been recently identified in familial amyotrophic lateral sclerosis (ALS). Functional studies performed on ALS-associated PFN1 mutants demonstrated aggregation propensity, alterations in growth cone, and cytoskeletal dynamics. Previous screening of PFN1 gene in sporadic ALS (SALS) cases led to the identification of the p.E117G mutation, which is likely to represent a less pathogenic variant according to both frequency data in control subjects and cases, and functional experiments. To determine the effective contribution of PFN1 mutations in SALS, we analyzed a large cohort of 1168 Italian SALS patients and also included 203 frontotemporal dementia (FTD) cases because of the great overlap between these 2 neurodegenerative diseases. We detected the p.E117G variant in 1 SALS patient and the novel synonymous change p.G15G in another patient, but none in a panel of 1512 control subjects. Our results suggest that PFN1 mutations in sporadic ALS and in FTD are rare, at least in the Italian population.
  Neurobiology of aging 10/2012; · 5.94 Impact Factor
• Article: Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis.

  Chi-Hong Wu, Claudia Fallini, Nicola Ticozzi, Pamela J Keagle, Peter C Sapp, Katarzyna Piotrowska, Patrick Lowe, Max Koppers, Diane McKenna-Yasek, Desiree M Baron, [......], Vincent Meininger, Wilfried Rossoll, Antonia Ratti, Cinzia Gellera, Daryl A Bosco, Gary J Bassell, Vincenzo Silani, Vivian E Drory, Robert H Brown, John E Landers
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  ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.
  Nature 07/2012; 488(7412):499-503. · 36.28 Impact Factor
• Article: C9ORF72 repeat expansion in a large Italian ALS cohort: evidence of a founder effect.

  Antonia Ratti, Lucia Corrado, Barbara Castellotti, Roberto Del Bo, Isabella Fogh, Cristina Cereda, Cinzia Tiloca, Carla D'Ascenzo, Alessandra Bagarotti, Viviana Pensato, [......], Mauro Ceroni, Gaia D Oggioni, Kuang Lin, John F Powell, Gianni Sorarù, Nicola Ticozzi, Giacomo P Comi, Sandra D'Alfonso, Cinzia Gellera, Vincenzo Silani
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  ABSTRACT: A hexanucleotide repeat expansion (RE) in C9ORF72 gene was recently reported as the main cause of amyotrophic lateral sclerosis (ALS) and cases with frontotemporal dementia. We screened C9ORF72 in a large cohort of 259 familial ALS, 1275 sporadic ALS, and 862 control individuals of Italian descent. We found RE in 23.9% familial ALS, 5.1% sporadic ALS, and 0.2% controls. Two cases carried the RE together with mutations in other ALS-associated genes. The phenotype of RE carriers was characterized by bulbar-onset, shorter survival, and association with cognitive and behavioral impairment. Extrapyramidal and cerebellar signs were also observed in few patients. Genotype data revealed that 95% of RE carriers shared a restricted 10-single nucleotide polymorphism haplotype within the previously reported 20-single nucleotide polymorphism risk haplotype, detectable in only 27% of nonexpanded ALS cases and in 28% of controls, suggesting a common founder with cohorts of North European ancestry. Although C9ORF72 RE segregates with disease, the identification of RE both in controls and in patients carrying additional pathogenic mutations suggests that penetrance and phenotypic expression of C9ORF72 RE may depend on additional genetic risk factors.
  Neurobiology of aging 07/2012; 33(10):2528.e7-14. · 5.94 Impact Factor
• Article: Oligoclonal bands in the cerebrospinal fluid of amyotrophic lateral sclerosis patients with disease-associated mutations.

  Nicola Ticozzi, Cinzia Tiloca, Niccolò E Mencacci, Claudia Morelli, Alberto Doretti, Daniela Rusconi, Claudia Colombrita, Davide Sangalli, Federico Verde, Palma Finelli, Stefano Messina, Antonia Ratti, Vincenzo Silani
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  ABSTRACT: In amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) analysis is usually performed to exclude inflammatory processes of the central nervous system. Although in a small subset of patients an intrathecal synthesis of IgG is detectable, usually there is no clear explanation for this evidence. This study investigates the occurrence of oligoclonal bands (OCBs) in the CSF of a large series of ALS patients, attempting a correlation with genotype data. CSF was collected from 259 ALS patients. CSF parameters were measured according to standard procedures, and detection of OCBs performed by isoelectric focusing. The patients were screened for mutations in SOD1, FUS, TARDBP, ANG, OPTN, and C9ORF72. We observed the presence of OCBs in the CSF of 9/259 ALS patients (3.5 %), and of disease-associated mutations in 12 cases. OCBs were significantly more frequent in mutation carriers compared to the remaining cohort (3/12 vs 6/247; p < 0.01). Among patients with OCBs, two patients had the TARDBP p.A382T mutation (one of which in homozygous state), and one the ANG p.P-4S variant. Both patients carrying the p.A382T mutation had an atypical phenotype, one of them manifesting signs suggestive of a cerebellar involvement, and the other presenting neuroradiological findings suggestive of an inflammatory disorder of the central nervous system. Our results suggest that ALS patients with OCBs may harbor mutations in disease-causing genes. We speculate that mutations in both TARDBP and ANG genes may disrupt the blood-brain barrier (BBB), promoting local immune responses and neuroinflammation. The role of mutant TARDBP and ANG genes on BBB integrity of ALS patients warrants further investigation.
  Journal of Neurology 07/2012; · 3.47 Impact Factor
• Source

  Available from: Pietro Cipresso

  Article: The use of P300-based BCIs in amyotrophic lateral sclerosis: from augmentative and alternative communication to cognitive assessment.

  Pietro Cipresso, Laura Carelli, Federica Solca, Daniela Meazzi, Paolo Meriggi, Barbara Poletti, Dorothée Lulé, Albert C Ludolph, Vincenzo Silani, Giuseppe Riva
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  ABSTRACT: The use of augmentative and alternative communication (AAC) tools in patients with amyotrophic lateral sclerosis (ALS), as effective means to compensate for the progressive loss of verbal and gestural communication, has been deeply investigated in the recent literature. The development of advanced AAC systems, such as eye-tracking (ET) and brain-computer interface (BCI) devices, allowed to bypass the important motor difficulties present in ALS patients. In particular, BCIs could be used in moderate to severe stages of the disease, since they do not require preserved ocular-motor ability, which is necessary for ET applications. Furthermore, some studies have proved the reliability of BCIs, regardless of the severity of the disease and the level of physical decline. However, the use of BCI in ALS patients still shows some limitations, related to both technical and neuropsychological issues. In particular, a range of cognitive deficits in most ALS patients have been observed. At the moment, no effective verbal-motor free measures are available for the evaluation of ALS patients' cognitive integrity; BCIs could offer a new possibility to administer cognitive tasks without the need of verbal or motor responses, as highlighted by preliminary studies in this field. In this review, we outline the essential features of BCIs systems, considering advantages and challenges of these tools with regard to ALS patients and the main applications developed in this field. We then outline the main findings with regard to cognitive deficits observed in ALS and some preliminary attempts to evaluate them by means of BCIs. The definition of specific cognitive profiles could help to draw flexible approaches tailored on patients' needs. It could improve BCIs efficacy and reduce patients' efforts. Finally, we handle the open question, represented by the use of BCIs with totally locked in patients, who seem unable to reliably learn to use such tool.
  Brain and behavior. 07/2012; 2(4):479-98.
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  Available from: Claire Troakes

  Article: The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder.

  Bradley N Smith, Stephen Newhouse, Aleksey Shatunov, Caroline Vance, Simon Topp, Lauren Johnson, Jack Miller, Younbok Lee, Claire Troakes, Kirsten M Scott, [......], Alex Morris, Jacqueline de Belleroche, J M B Vianney de Jong, Frank Baas, Peter M Andersen, John Landers, Robert H Brown, Michael E Weale, Ammar Al-Chalabi, Christopher E Shaw
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  ABSTRACT: A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.European Journal of Human Genetics advance online publication, 13 June 2012; doi:10.1038/ejhg.2012.98.
  European journal of human genetics: EJHG 06/2012; · 3.56 Impact Factor
• Article: Molecular Signatures of Amyotrophic Lateral Sclerosis Disease Progression in Hind and Forelimb Muscles of an SOD1(G93A) Mouse Model.

  Daniele Capitanio, Michele Vasso, Antonia Ratti, Giuliano Grignaschi, Manuela Volta, Manuela Moriggi, Cristina Daleno, Caterina Bendotti, Vincenzo Silani, Cecilia Gelfi
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  ABSTRACT: Abstract Aims: This study utilized proteomics, biochemical and enzymatic assays, and bioinformatics tools that characterize protein alterations in hindlimb (gastrocnemius) and forelimb (triceps) muscles in an amyotrophic lateral sclerosis (ALS) (SOD1(G93A)) mouse model. The aim of this study was to identify the key molecular signatures involved in disease progression. Results: Both muscle types have in common an early down-regulation of complex I. In the hindlimb, early increases in oxidative metabolism are associated with uncoupling of the respiratory chain, an imbalance of NADH/NAD(+), and an increase in reactive oxygen species (ROS) production. The NADH overflow due to complex I inactivation induces TCA flux perturbations, leading to citrate production, triggering fatty acid synthase (FAS), and lipid peroxidation. These early metabolic changes in the hindlimb followed by sustained and comparatively higher metabolic and cytoskeletal derangements over time precede and may catalyze the progressive muscle wasting in this muscle at the late stage. By contrast, in the forelimb, there is an early down-regulation of complexes I and II that is associated with the reduction of oxidative metabolism, which promotes metabolic homeostasis that is accompanied by a greater cytoskeletal stabilization response. However, these early compensatory systems diminish by a later time point. Innovation: The identification of potential early- and late-stage disease molecular signatures in an ALS model: muscle albumin, complex I, complex II, citrate synthase, FAS, and phosphoinositide 3-kinase functions as diagnostic markers and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α), Sema-3A, and Rho-associated protein kinase 1 (ROCK1) play the role of disease progression markers. Conclusion: The differing pattern of cellular metabolism and cytoskeletal derangements in the hind and forelimb identifies the potential dysmetabolism/hypermetabolism molecular signatures associated with disease progression, which may serve as diagnostic/disease progression markers in ALS patients. Antioxid. Redox Signal. 17, 1333-1350.
  Antioxidants & Redox Signaling 05/2012; 17(10):1333-50. · 8.20 Impact Factor
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  Available from: Emanuele Buratti

  Article: TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells.

  Claudia Colombrita, Elisa Onesto, Francesca Megiorni, Antonio Pizzuti, Francisco E Baralle, Emanuele Buratti, Vincenzo Silani, Antonia Ratti
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  ABSTRACT: The RNA-binding proteins TDP-43 and FUS form abnormal cytoplasmic aggregates in affected tissues of patients with amyotrophic lateral sclerosis and frontotemporal lobar dementia. TDP-43 and FUS localize mainly in the nucleus where they regulate pre-mRNA splicing, but they are also involved in mRNA transport, stability, and translation. To better investigate their cytoplasmic activities, we applied an RNA immunoprecipitation and chip analysis to define the mRNAs associated to TDP-43 and FUS in the cytoplasmic ribonucleoprotein complexes from motoneuronal NSC-34 cells. We found that they bind different sets of mRNAs although converging on common cellular pathways. Bioinformatics analyses identified the (UG)(n) consensus motif in 80% of 3'-UTR sequences of TDP-43 targets, whereas for FUS the binding motif was less evident. By in vitro assays we validated binding to selected target 3'-UTRs, including Vegfa and Grn for TDP-43, and Vps54, Nvl, and Taf15 for FUS. We showed that TDP-43 has a destabilizing activity on Vegfa and Grn mRNAs and may ultimately affect progranulin protein content, whereas FUS does not affect mRNA stability/translation of its targets. We also demonstrated that three different point mutations in TDP-43 did not change the binding affinity for Vegfa and Grn mRNAs or their protein level. Our data indicate that TDP-43 and FUS recognize distinct sets of mRNAs and differently regulate their fate in the cytoplasm of motoneuron-like cells, therefore suggesting complementary roles in neuronal RNA metabolism and neurodegeneration.
  Journal of Biological Chemistry 03/2012; 287(19):15635-47. · 4.77 Impact Factor
• Article: ATAXIN2 CAG-repeat length in Italian patients with amyotrophic lateral sclerosis: risk factor or variant phenotype? Implication for genetic testing and counseling.

  Cinzia Gellera, Nicola Ticozzi, Viviana Pensato, Lorenzo Nanetti, Alessia Castucci, Barbara Castellotti, Giuseppe Lauria, Franco Taroni, Vincenzo Silani, Caterina Mariotti
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  ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly involving cortical and spinal motor neurons. Several studies indicated that intermediate CAG expansions in ataxin-2 gene (ATXN2) are associated with increased risk of ALS. We analyzed ATXN2 CAG repeats in 658 sporadic ALS patients (SALS), 143 familial ALS cases (FALS), 231 sporadic ataxic subjects, and 551 control subjects. The frequency of ATXN2 alleles with 27-30 repeats was similar in SALS and control subjects. Fifteen SALS subjects carried ≥ 31 CAG repeats. This difference was statistically significant (p = 0.0014). No alleles with ≥ 34 CAG were found. In FALS, the distribution of ATXN2 alleles was similar to control subjects. Our results further contributed in refining CAG-repeat range significantly associated with sporadic ALS. Literature data and our findings indicate that only alleles with ≥ 31 CAG may represent low-penetrance disease/susceptibility alleles associated with variable neurodegenerative phenotypes, including cerebellar ataxia, parkinsonism, and ALS. Overlapping phenotypes should be considered in genetic testing and counseling, both for patients and at-risk family members.
  Neurobiology of aging 03/2012; 33(8):1847.e15-21. · 5.94 Impact Factor
• Article: Prevalence of Huntington's disease gene CAG repeat alleles in sporadic amyotrophic lateral sclerosis patients.

  Eliana Marisa Ramos, Pamela Keagle, Tammy Gillis, Patrick Lowe, Jayalakshmi S Mysore, Ashley Lyn Leclerc, Antonia Ratti, Nicola Ticozzi, Cinzia Gellera, James F Gusella, Vincenzo Silani, Isabel Alonso, Robert H Brown, Marcy E MacDonald, John E Landers
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  ABSTRACT: A higher prevalence of intermediate ataxin-2 CAG repeats in amyotrophic lateral sclerosis (ALS) patients has raised the possibility that CAG expansions in other polyglutamine disease genes could contribute to ALS neurodegeneration. We sought to determine whether expansions of the CAG repeat of the HTT gene that causes Huntington's disease, are associated with ALS. We compared the HTT CAG repeat length on a total of 3144 chromosomes from 1572 sporadic ALS patients and 4007 control chromosomes, and also tested its possible effects on ALS-specific parameters, such as age and site of onset and survival rate. Our results show that the CAG repeat in the HTT gene is not a risk factor for ALS nor modifies its clinical presentation. These findings suggest that distinct neuronal degeneration processes are involved in these two different neurodegenerative disorders.
  Amyotrophic Lateral Sclerosis 03/2012; 13(3):265-9. · 3.40 Impact Factor
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  Available from: Elena Dozio

  Article: Impaired expression of insulin-like growth factor-1 system in skeletal muscle of amyotrophic lateral sclerosis patients.

  Christian Lunetta, Massimo Serafini, Alessandro Prelle, Paolo Magni, Elena Dozio, Massimiliano Ruscica, Jenny Sassone, Clarissa Colciago, Maurizio Moggio, Massimo Corbo, Vincenzo Silani
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  ABSTRACT: Adult muscle fibers are a source of growth factors, including insulin-like growth factor-1 (IGF-1). These factors influence neuronal survival, axonal growth, and maintenance of synaptic connections. We investigated the components of the IGF system in skeletal muscle samples obtained from 17 sporadic amyotrophic lateral sclerosis patients (sALS) and 29 control subjects (17 with normal muscle and 12 with denervated muscle unrelated to ALS). The muscle expression of IGF-1 and IGF-binding proteins 3, 4, and 5 (IGF-BP3, -4, and -5, respectively), assessed by immunohistochemistry, was differently decreased in sALS compared with both control groups; conversely, IGF-1 receptor β subunit (IGF-1Rβ) was significantly increased. Western blot analysis confirmed the severe reduction of IGF-1, IGF-BP3, and -BP5 with the increment of IGF-1Rβ in sALS. In this study we describe the abnormal expression of the IGF-1 system in skeletal muscle of sALS patients that could participate in motor neuron degeneration and should be taken into account when developing treatments with IGF-1.
  Muscle & Nerve 02/2012; 45(2):200-8. · 2.37 Impact Factor
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  Available from: Cinzia Calzarossa

  Article: Neuroprotective effects of human mesenchymal stem cells on neural cultures exposed to 6-hydroxydopamine: implications for reparative therapy in Parkinson's disease.

  Lidia Cova, Patrizia Bossolasco, Marie-Therese Armentero, Valentina Diana, Eleonora Zennaro, Manuela Mellone, Cinzia Calzarossa, Silvia Cerri, Giorgio Lambertenghi Deliliers, Elio Polli, Fabio Blandini, Vincenzo Silani
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  ABSTRACT: Stem cell (SC) transplantation represents a promising tool to treat neurodegenerative disorders, such as Parkinson's disease (PD), but positive therapeutic outcomes require elucidation of the biological mechanisms involved. Therefore, we investigated human Mesenchymal SCs (hMSCs) ability to protect murine differentiated Neural SCs (mdNSCs) against the cytotoxic effects of 6-hydroxydopamine (6-OHDA) in a co-culture model mimicking the in vivo neurovascular niche. The internalization of 6-OHDA mainly relies on its uptake by the dopamine active transporter (DAT), but its toxicity could also involve other pathways. We demonstrated that mdNSCs consistently expressed DAT along the differentiative process. Exposure to 6-OHDA did not affect hMSCs, but induced DAT-independent apoptosis in mdNSCs with generation of reactive oxygen species and caspases 3/7 activation. The potential neuroprotective action of hMSCs on mdNSCs exposed to 6-OHDA was tested in different co-culture conditions, in which hMSCs were added to mdNSCs prior to, simultaneously, or after 6-OHDA treatment. In the presence of the neurotoxin, the majority of mdNSCs acquired an apoptotic phenotype, while co-cultures with hMSCs significantly increased their survival (up to 70%) in all conditions. Multiplex human angiogenic array analysis on the conditioned media demonstrated that cytokine release by hMSCs was finely modulated. Moreover, sole growth factor addition yielded a similar neuroprotective effect on mdNSCs. In conclusion, our findings demonstrate that hMSCs protect mdNSCs against 6-OHDA neurotoxicity, and rescue cells from ongoing neurodegeneration likely through the release of multiple cytokines. Our findings provide novel insights for the development of therapeutic strategies designed to counteract the neurodegenerative processes of PD.
  Apoptosis 12/2011; 17(3):289-304. · 4.07 Impact Factor
• Article: Mutational analysis of VCP gene in familial amyotrophic lateral sclerosis.

  Cinzia Tiloca, Antonia Ratti, Viviana Pensato, Alessia Castucci, Gianni Sorarù, Roberto Del Bo, Lucia Corrado, Cristina Cereda, Carla D'Ascenzo, Giacomo P Comi, Letizia Mazzini, Barbara Castellotti, Nicola Ticozzi, Cinzia Gellera, Vincenzo Silani
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  ABSTRACT: Mutations in valosin-containing protein (VCP) gene, already known to be associated with the multisystemic disorder, inclusion body myopathy with Paget's disease and frontotemporal dementia (IBMPFD), have been recently found also in familial cases of amyotrophic lateral sclerosis (ALS). To further define the frequency of VCP mutations in ALS Italian population, we screened a cohort of 166 familial ALS and 14 ALS-frontotemporal dementia (FTD) individuals. We identified a previously reported synonymous mutation (c.2093A>C; p.Q568Q), 2 intronic variants (c.1749-14C>T; c.2085-3C>T), and 1 nucleotide change (c.2814G>T) in the 3' untranslated region (UTR). Bioinformatical analyses predicted no changes in splicing process or microRNA binding sites. Our results do not confirm a main contribution of VCP gene to familial ALS in the Italian population.
  Neurobiology of aging 12/2011; 33(3):630.e1-2. · 5.94 Impact Factor