Latest PUBLICATIONS

  • Novel mutations in <i>dystonin</i> provide clues to the pathomechanisms of HSAN-VI.
    Publication Date: 30/05/2017, on Neurology
    by Manganelli F, Parisi S, Nolano M, Tao F, Paladino S, Pisciotta C, Tozza S, Nesti C, Rebelo AP, Provitera V, Santorelli FM, Shy ME, Russo T, Zuchner S, Santoro L
    DOI: 10.1212/WNL.0000000000003992

    To describe a second hereditary sensory autonomic neuropathy type VI (HSAN-VI) family harboring 2 novel heterozygous mutations in the dystonin (DST) gene and to evaluate their effect on neurons derived from induced pluripotent stem cells (iPSC).

  • Cognitive impairment is associated with Hoehn and Yahr stages in early, de novo Parkinson disease patients.
    Publication Date: 25/05/2017, on Parkinsonism & related disorders
    by Siciliano M, De Micco R, Trojano L, De Stefano M, Baiano C, Passaniti C, De Mase A, Russo A, Tedeschi G, Tessitore A
    DOI: 10.1016/j.parkreldis.2017.05.020

    The relationship between motor impairment and cognitive deterioration has long been described in Parkinson's disease (PD). The aim of the study was to compare cognitive performance of de novo PD patients in relation to the motor impairment severity according to Hoehn and Yahr (HY) stages.

  • Whose hand is this? Differential responses of right and left extrastriate body areas to visual images of self and others' hands.
    Publication Date: 23/05/2017, on Cognitive, affective & behavioral neuroscience
    by De Bellis F, Trojano L, Errico D, Grossi D, Conson M
    DOI: 10.3758/s13415-017-0514-z

    The extrastriate body area (EBA) is involved in perception of human bodies and nonfacial body parts, but its role in representing body identity is not clear. Here, we used on-line high-frequency repetitive transcranial magnetic stimulation (rTMS) to test the role of EBA in self-other distinction. In Experiments 1 and 2 we compared rTMS of right EBA with stimulation of left ventral premotor cortex (vPM), whereas in Experiment 3 we compared stimulation of right and left EBA. RTMS was applied during a hand laterality task in which self or others' hand images were presented in first- versus third-person view (Experiments 1 and 3), or while participants had to explicitly recognize their own hands (Experiment 2) presented in first- versus third-person view. Experiment 1 showed that right EBA stimulation selectively speeded judgments on others' hands, whereas no effect of left vPM stimulation was found. Experiment 2 did not reveal any effect of rTMS. Experiment 3 confirmed faster responses on others' hands while stimulating right EBA and also showed an advantage when judging self with respect to others' hands during stimulation of left EBA. These results would demonstrate that EBA responds to morphological features of human body contributing to identity processing.

  • Resveratrol protects neuronal-like cells expressing mutant Huntingtin from dopamine toxicity by rescuing ATG4-mediated autophagosome formation.
    Publication Date: 19/05/2017, on Neurochemistry international
    by Vidoni C, Secomandi E, Castiglioni A, Melone MAB, Isidoro C
    DOI: 10.1016/j.neuint.2017.05.013

    Parkinsonian-like motor deficits in Huntington's Disease (HD) patients are associated with abnormal dopamine neurotransmission in the striatum. Dopamine metabolism leads to the formation of oxidized dopamine quinones that exacerbates mitochondrial dysfunction with production of reactive oxygen species (ROS) that eventually lead to neuronal cell death. We have previously shown that dopamine-induced oxidative stress triggers apoptotic cell death in dopaminergic neuroblastoma SH-SY5Y cells hyper-expressing the mutant polyQ Huntingtin (polyQ-Htt) protein. Dopamine toxicity was paralleled by impaired autophagy clearance of the polyQ-Htt aggregates. In this study, we found that Dopamine affects the stability and function of ATG4, a redox-sensitive cysteine-protein involved in the processing of LC3, a key step in the formation of autophagosomes. Resveratrol, a dietary polyphenol with anti-oxidant and pro-autophagic properties, has shown neuroprotective potential in HD. Yet the molecular mechanism through which Resveratrol can protect HD cells against DA is not known. Here, we show that Resveratrol prevents the generation of ROS, restores the level of ATG4, allows the lipidation of LC3, facilitates the degradation of polyQ-Htt aggregates and protects the cells from Dopamine toxicity. The present findings provide a mechanistic explanation of the neuroprotective activity of Resveratrol and support its inclusion in a therapeutic regimen to slow down HD progression.

  • Modified Denatured Lysozyme Effectively Solubilizes Fullerene C60 Nanoparticles in Water.
    Publication Date: 19/05/2017, on Nanotechnology
    by Siepi M, Politi J, Dardano P, Amoresano A, De Stefano L, Monti DM, Notomista E
    DOI: 10.1088/1361-6528/aa744e

    Fullerenes, allotropic forms of carbon, have very interesting pharmacological effects and engineering applications. However, a very low solubility both in organic solvents and water hinders their use. Fullerene C60, the most studied among fullerenes, can be dissolved in water only in the form of nanoparticles of variable dimensions and limited stability. Here the effect on the production of C60 nanoparticles by native and denatured hen egg white lysozyme, a highly basic protein, has been systematically studied. In order to obtain a denatured, yet soluble, lysozyme derivative, the four disulfides of the native protein were reduced and exposed cysteines were alkylated by 3-bromopropylamine, thus introducing eight additional positive charges. The C60 solubilizing properties of the modified denatured lysozyme proved to be superior to those of the native protein, allowing to prepare biocompatible high homogeneous and stable C60 nanoparticles using lower amounts of protein as demonstrated by dynamic light scattering, transmission electron microscopy and atomic force microscopy studies. This lysozyme derivative could represent an effective tool for the solubilization of other carbon allotropes.

  • Multilayer microstructure of idiopathic epiretinal macular membranes.
    Publication Date: 19/05/2017, on European journal of ophthalmology
    by Azzolini C, Congiu T, Donati S, Passi A, Basso P, Piantanida E, Mariotti C, Testa F, Caprani SM, Cattaneo J, Vinciguerra R
    DOI: 10.5301/ejo.5000982

    To identify the ultramicroscopic structure of idiopathic epiretinal macular membranes (iEMMs) by scanning electron microscopy (SEM).

  • Starvation Promotes Autophagy-Associated Maturation of the Ovary in the Giant Freshwater Prawn, <i>Macrobrachium rosenbergii</i>.
    Publication Date: 12/05/2017, on Frontiers in physiology
    by Kankuan W, Wanichanon C, Titone R, Engsusophon A, Sumpownon C, Suphamungmee W, Morani F, Masini M, Novelli M, Isidoro C, Sobhon P
    DOI: 10.3389/fphys.2017.00300

    Limitation of food availability (starvation) is known to influence the reproductive ability of animals. Autophagy is a lysosomal driven degradation process that protects the cell under metabolic stress conditions, such as during nutrient shortage. Whether, and how starvation-induced autophagy impacts on the maturation and function of reproductive organs in animals are still open questions. In this study, we have investigated the effects of starvation on histological and cellular changes that may be associated with autophagy in the ovary of the giant freshwater prawn, Macrobachium rosenbergii. To this end, the female prawns were daily fed (controls) or unfed (starvation condition) for up to 12 days, and the ovary tissue was analyzed at different time-points. Starvation triggered ovarian maturation, and concomitantly increased the expression of autophagy markers in vitellogenic oocytes. The immunoreactivities for autophagy markers, including Beclin1, LC3-II, and Lamp1, were enhanced in the late oocytes within the mature ovaries, especially at the vitellogenic stages. These markers co-localized with vitellin in the yolk granules within the oocytes, suggesting that autophagy induced by starvation could drive vitellin utilization, thus promoting ovarian maturation.

  • A comparison study on RNase A oligomerization induced by cisplatin, carboplatin and oxaliplatin.
    Publication Date: 09/05/2017, on Journal of inorganic biochemistry
    by Picone D, Donnarumma F, Ferraro G, Gotte G, Fagagnini A, Butera G, Donadelli M, Merlino A
    DOI: 10.1016/j.jinorgbio.2017.05.005

    Cisplatin (CDDP) can form interprotein cross-links, leading to the formation of platinated oligomers. A dimer, a trimer and higher oligomers of bovine pancreatic ribonuclease (RNase A) obtained upon reaction with CDDP in 1:10 protein to metal ratio at 37°C have been previously characterized. Here, we verify the ability of carboplatin and oxaliplatin to induce RNase A oligomerization under the same experimental conditions. The amount of formed RNase A oligomers was compared with that obtained in the reaction of the protein with CDDP. Among the three anticancer agents, CDDP is the most reactive and the most effective in inhibiting the ribonucleolytic activity of the protein. Oxaliplatin is the least potent oligomerization agent. Biophysical characterizations of structure and stability of platinated dimers formed in the presence of carboplatin and oxaliplatin suggest that they have a similar thermal stability and are more prone to dissociation than the corresponding dimer obtained with CDDP. Oligomers obtained in the presence of carboplatin are the most active. X-ray structures of the monomeric adducts that RNase A forms with the three drugs provide a rational basis to explain the different effects of the three anticancer agents on enzymatic activity and protein aggregation. Although platinated oligomers of RNase A formed upon reaction with CDDP, carboplatin and oxaliplatin retain a residual ribonuclease activity, they do not show cytotoxic action, suggesting that protein aggregation processes induced by Pt-based drugs can represent a collateral drawback, which affects the functional state of protein targets and reduces the efficacy of Pt-based drug treatment.

  • Functional characterization of the neuron-restrictive silencer element in the human tryptophan hydroxylase 2 gene expression.
    Publication Date: 02/05/2017, on Journal of neurochemistry
    by Nawa Y, Kaneko H, Oda M, Tsubonoya M, Hiroi T, Gentile MT, Colucci-D'Amato L, Takahashi R, Matsui H
    DOI: 10.1111/jnc.14060

    Tryptophan hydroxylase 2 (TPH2) is the key enzyme in the synthesis of neuronal serotonin. Although previous studies suggest that TPH2 NRSE (neuron-restrictive silencer element) functions as a negative regulator dependent on NRSF (neuron-restrictive silencer factor) activity, the underlying mechanisms are yet to be fully elucidated. Here, we show a detailed analysis of the NRSE-mediated repression of the human TPH2 (hTPH2) promoter activity in RN46A cells, a cell line derived from rat raphe neurons. Quantitative real-time RT-PCR analysis revealed the expression of serotonergic marker genes (Mash1, Nkx2.2, Gata2, Gata3, Lmx1b, Pet-1, 5-Htt, and Vmat2) and Nrsf gene in RN46A cells. Tph1 mRNA is the prevalent form expressed in RN46A cells; Tph2 mRNA is also expressed but at a lower level. Electrophoretic mobility shift assays and reporter assays showed that hTPH2 NRSE is necessary for the efficient DNA binding of NRSF and for the NRSF-dependent repression of the hTPH2 promoter activity. The hTPH2 promoter activity was increased by knockdown of NRSF, or overexpression of the engineered NRSF (a dominant-negative mutant or a DNA-binding domain and activation domain fusion protein). MS-275, a class I histone deacetylase (HDAC) inhibitor, was found to be more potent than MC-1568, a class II HDAC inhibitor, in enhancing the hTPH2 promoter activity. Furthermore, treatment with the ubiquitin-specific protease 7 (USP7) deubiquitinase inhibitors, P-22077 or HBX 41108, increased the hTPH2 promoter activity. Collectively, our data demonstrate that the hTPH2 NRSE-mediated promoter repression via NRSF involves class I HDACs and is modulated by the USP7-mediated deubiquitination and stabilization of NRSF. This article is protected by copyright. All rights reserved.

  • Squid Giant Axons Synthesize NF Proteins.
    Publication Date: 02/05/2017, on Molecular neurobiology
    by Crispino M, Chun JT, Giuditta A
    DOI: 10.1007/s12035-017-0561-z

    Squid giant axon has been an excellent model system for studying fundamental topics in neurobiology such as neuronal signaling. It has been also useful in addressing the questions of local protein synthesis in the axons. Incubation of isolated squid giant axons with [(35)S]methionine followed by immunoprecipitation with a rabbit antibody against all squid neurofilament (NF) proteins demonstrates the local synthesis of a major 180 kDa NF protein and of several NF proteins of lower molecular weights. Their identification as NF proteins is based on their absence in the preimmune precipitates. Immunoprecipitates washed with more stringent buffers confirmed these results. Our data are at variance with a recent study based on the same experimental procedure that failed to visualize the local synthesis of NF proteins by the giant axon and thereby suggested their exclusive derivation from nerve cell bodies (as reported by Gainer et al. in Cell Mol Neurobiol 37:475-486, 2017). By reviewing the pertinent literature, we confute the claims that mRNA translation is absent in mature axons because of a putative translation block and that most proteins of mature axons are synthesized in the surrounding glial cells. Given the intrinsic axonal capacity to synthesize proteins, we stress the glial derivation of axonal and presynaptic RNAs and the related proposal that these neuronal domains are endowed with largely independent gene expression systems (as reported by Giuditta et al. in Physiol Rev 88:515-555, 2008).

  • Wearable Improved Vision System for Color Vision Deficiency Correction.
    Publication Date: 02/05/2017, on IEEE journal of translational engineering in health and medicine
    by Melillo P, Riccio D, Di Perna L, Sanniti Di Baja G, De Nino M, Rossi S, Testa F, Simonelli F, Frucci M
    DOI: 10.1109/JTEHM.2017.2679746

    Color vision deficiency (CVD) is an extremely frequent vision impairment that compromises the ability to recognize colors. In order to improve color vision in a subject with CVD, we designed and developed a wearable improved vision system based on an augmented reality device. The system was validated in a clinical pilot study on 24 subjects with CVD (18 males and 6 females, aged 37.4 ± 14.2 years). The primary outcome was the improvement in the Ishihara Vision Test score with the correction proposed by our system. The Ishihara test score significantly improved ([Formula: see text]) from 5.8 ± 3.0 without correction to 14.8 ± 5.0 with correction. Almost all patients showed an improvement in color vision, as shown by the increased test scores. Moreover, with our system, 12 subjects (50%) passed the vision color test as normal vision subjects. The development and preliminary validation of the proposed platform confirm that a wearable augmented-reality device could be an effective aid to improve color vision in subjects with CVD.

  • Intracardiac metastasis originated from chondrosarcoma.
    Publication Date: 01/05/2017, on Journal of cardiovascular medicine (Hagerstown, Md.)
    by Maurea N, Ragone G, Coppola C, Caronna A, Tocchetti CG, Agozzino L, Apice G, Iaffaioli RV
    DOI: 10.2459/JCM.0b013e32834165eb

    Primary cardiac tumors are extremely rare. By comparison, metastatic involvement of the heart is over 20 times more common and has been reported in autopsy series in up to one in five patients dying of cancer. Cardiac metastasis of chondrosarcoma is absolutely not frequent. In the recent literature, a cardiac metastasis from chondrosarcoma has never been described. We report the case of an 18-year-old man with a diagnosis of cardiac metastasis that originated from a left scapular chondrosarcoma. Chondrosarcoma is a skeletal tumor with various grades of malignancy, rapidly evolving, and with a strong tendency to metastasize, with low responsiveness to chemotherapy. The onset of characteristic systemic symptoms in the late stage of the disease led to the diagnosis of a mass localized in the right atrium. Management and differential diagnosis of infective heart lesions were also very complex in a rapidly evolving life-threatening condition.

  • Multiple pathways of SIRT6 at the crossroads in the control of longevity, cancer, and cardiovascular diseases.
    Publication Date: 01/05/2017, on Ageing research reviews
    by Vitiello M, Zullo A, Servillo L, Mancini FP, Borriello A, Giovane A, Della Ragione F, D'Onofrio N, Balestrieri ML
    DOI: 10.1016/j.arr.2016.10.008

    Sirtuin 6 (SIRT6) is a member of the sirtuin family NAD+-dependent deacetylases with multiple roles in controlling organism homeostasis, lifespan, and diseases. Due to its complex and opposite functional roles, this sirtuin is considered a two-edged sword in health and disease. Indeed, SIRT6 improves longevity, similarly to the founding yeast member, silent information regulator-2 (Sir2), and modulates genome stability, telomere integrity, transcription, and DNA repair. Its deficiency is associated with chronic inflammation, diabetes, cardiac hypertrophy, obesity, liver dysfunction, muscle/adipocyte disorders, and cancer. Besides, pieces of evidence showed that SIRT6 is a promoter of specific oncogenic pathways, thus disclosing its dual role regarding cancer development. Collectively, these findings suggest that multiple mechanisms, to date not entirely known, underlie the intriguing roles of SIRT6. Here we provide an overview of the current molecular mechanisms through which SIRT6 controls cancer and heart diseases, and describe its recent implications in the atherosclerotic plaque development.

  • GRN deletion in familial frontotemporal dementia showing association with clinical variability in 3 familial cases.
    Publication Date: 01/05/2017, on Neurobiology of aging
    by Milan G, Napoletano S, Pappatà S, Gentile MT, Colucci-D'Amato L, Della Rocca G, Maciag A, Rossetti CP, Fucci L, Puca A, Grossi D, Postiglione A, Vitale E
    DOI: 10.1016/j.neurobiolaging.2016.12.030

    Progranulin (GRN) gene mutations have been genetically associated with frontotemporal dementia (FTD) and are present in about 23% of patients with familial FTD. However, the neurobiology of this secreted glycoprotein remains unclear. Here, we report the identification of 3 pedigrees of Southern Italian extraction in whom FTD segregates with autosomal dominant inheritance patterns. We present evidence that all the available patients in these 3 familial cases are carrying the rare GRN gene exon 6 deletion g10325_10331delCTGCTGT (relative to nt 1 inNG_007886.1), alias Cys157LysfsX97. This mutation was previously described in 2 sporadic cases but was never associated with familial cases. Our patients demonstrate heterogeneous clinical phenotypes, such as the behavioral variant (bvFTD) in the affected men and the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) in the affected woman. Haploinsufficiency was revealed by both quantitative real-time PCR of the gene and protein analyses. These findings provide further support for a previously proposed role for the GRN gene in the genetic etiology of FTD and its phenotypic variability.

  • Lead Discovery of Dual G-Quadruplex Stabilizers and Poly(ADP-ribose) Polymerases (PARPs) Inhibitors: A New Avenue in Anticancer Treatment.
    Publication Date: 01/05/2017, on Journal of medicinal chemistry
    by Salvati E, Botta L, Amato J, Di Leva FS, Zizza P, Gioiello A, Pagano B, Graziani G, Tarsounas M, Randazzo A, Novellino E, Biroccio A, Cosconati S
    DOI: 10.1021/acs.jmedchem.6b01563

    G-quadruplex stabilizers are an established opportunity in anticancer chemotherapy. To circumvent the antiproliferative effects of G4 ligands, cancer cells recruit PARP enzymes at telomeres. Herein, starting from the structural similarity of a potent G4 ligand previously discovered by our group and a congeneric PARP inhibitor, a library of derivatives was synthesized to discover the first dual G4/PARP ligand. We demonstrate that a properly decorated thieno[3,2-c]quinolin-4(5H)-one stabilizes the G4 fold in vitro and in cells, induces a DNA damage response localized to telomeres, inhibits PARylation in cells, and has an antiproliferative effect in BRCA2 deficient tumor cells.