المؤلفون: Scarabino D., Veneziano L., Mantuano E., Arisi I., Fiore A., Frontali M., Corbo R. M.

المساهمون: Scarabino, D., Veneziano, L., Mantuano, E., Arisi, I., Fiore, A., Frontali, M., Corbo, R. M.

مصطلحات موضوعية: Huntington’s disease, fluid biomarker, leukocyte telomere length, neurodegenerative diseases

الوصف: The identification of biomarkers for neurodegenerative disorders such as Huntington's disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39-51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/36362235; info:eu-repo/semantics/altIdentifier/wos/WOS:000883909800001; volume:23; issue:21; numberofpages:11; journal:INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; https://hdl.handle.net/11573/1672553Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85141853493

الإتاحة: https://doi.org/10.3390/ijms232113449Test
https://hdl.handle.net/11573/1672553Test

المؤلفون: Scarabino D., Veneziano L., Fiore A., Nethisinghe S., Mantuano E., Garcia-Moreno H., Bellucci G., Solanky N., Morello M., Zanni G., Corbo R. M., Giunti P.

المساهمون: Scarabino, D., Veneziano, L., Fiore, A., Nethisinghe, S., Mantuano, E., Garcia-Moreno, H., Bellucci, G., Solanky, N., Morello, M., Zanni, G., Corbo, R. M., Giunti, P.

مصطلحات موضوعية: biomarker, leukocyte telomere length, neurodegenerative disease, spinocerebellar ataxias

الوصف: SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington's Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient's age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/35892638; info:eu-repo/semantics/altIdentifier/wos/WOS:000846350400001; volume:11; issue:8; numberofpages:16; journal:ANTIOXIDANTS; https://hdl.handle.net/11573/1672546Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85137356474

الإتاحة: https://doi.org/10.3390/antiox11081436Test
https://hdl.handle.net/11573/1672546Test

المؤلفون: Mattei V., Manganelli V., Martellucci S., Capozzi A., Mantuano E., Longo A., Ferri A., Garofalo T., Sorice M., Misasi R.

المساهمون: Mattei, V., Manganelli, V., Martellucci, S., Capozzi, A., Mantuano, E., Longo, A., Ferri, A., Garofalo, T., Sorice, M., Misasi, R.

مصطلحات موضوعية: GM1, lipid raft, LRP1, methyl-β-cyclodextrin, prion protein, tPA

الوصف: Prion protein (PrPC) localizes stably in lipid rafts microdomains and is able to recruit downstream signal transduction pathways by the interaction with promiscuous partners. Other proteins have the ability to occasionally be recruited to these specialized membrane areas, within multimolecular complexes. Among these, we highlight the presence of the low-density lipoprotein receptor-related protein 1 (LRP1), which was found localized transiently in lipid rafts, suggesting a different function of this receptor that through lipid raft becomes able to activate a signal transduction pathway triggered by specific ligands, including Tissue plasminogen activator (tPA). Since it has been reported that PrPC participates in the tPA-mediated plasminogen activation, in this study, we describe the role of lipid rafts in the recruitment and activation of downstream signal transduction pathways mediated by the interaction among tPA, PrPC and LRP1 in human neuroblastoma SK-N-BE2 cell line. Co-immunoprecipitation analysis reveals a consistent association between PrPC and GM1, as well as between LRP1 and GM1, indicating the existence of a glycosphingolipid-enriched multimolecular complex. In our cell model, knocking-down PrPC by siRNA impairs ERK phosphorylation induced by tPA. Moreover the alteration of the lipidic milieu of lipid rafts, perturbing the physical/functional interaction between PrPC and LRP1, inhibits this response. We show that LRP1 and PrPC, following tPA stimulation, may function as a system associated with lipid rafts, involved in receptor-mediated neuritogenic pathway. We suggest this as a multimolecular signaling complex, whose activity depends strictly on the integrity of lipid raft and is involved in the neuritogenic signaling. (Figure presented.).

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/31602645; info:eu-repo/semantics/altIdentifier/wos/WOS:000492387700001; volume:152; issue:4; firstpage:468; lastpage:481; numberofpages:14; journal:JOURNAL OF NEUROCHEMISTRY; http://hdl.handle.net/11573/1403166Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85074630969

الإتاحة: https://doi.org/10.1111/jnc.14891Test
http://hdl.handle.net/11573/1403166Test

المؤلفون: Scarabino D., Peconi M., Broggio E., Gambina G., Maggi E., Armeli F., Mantuano E., Morello M., Corbo R. M., Businaro R.

المساهمون: Scarabino, D., Peconi, M., Broggio, E., Gambina, G., Maggi, E., Armeli, F., Mantuano, E., Morello, M., Corbo, R. M., Businaro, R.

مصطلحات موضوعية: Alzheimer's disease, IL-18, IL-1beta, Leukocyte telomere length, Mild cognitive impairment

الوصف: Inflammation plays a crucial role in Alzheimer's disease (AD). AD neurodegeneration and concurrent involvement of the peripheral immune system may promote leukocyte division and telomere shortening. We examined genotypes and plasma levels of two proinflammatory cytokines, IL-1beta and IL-18, and leukocyte telomere length (LTL) in patients with mild cognitive impairment (MCI) and AD. We wanted to determine whether changes in plasma IL-1beta and IL-18 levels, together with LTL shortening, could be diagnostic for disease progression from MCI to AD. Median plasma IL-1beta levels were in the order MCI patients (2.2 pg/ml) < AD patients (4.0 pg/ml), both of which differed significantly from the controls (0.0 pg/ml). In the AD patients, the lowest IL-1beta levels were associated with the presence of the C allele of IL-1beta rs16944 SNP. Median plasma IL-18 levels were in the order MCI patients (116.3 pg/ml) > AD patients (85.8 pg/ml), both of which were significantly higher than in the controls (17.6 pg/ml). Analysis of LTL showed a progressive reduction in the order controls > MCI > AD patients (p < 0.0001). Overall LTL reduction was correlated with increased plasma IL-1beta levels, substantiating the hypothesis that inflammatory processes secondary to neuroinflammation may trigger telomere attrition. Changes in plasma IL-1beta and Il-18 levels, and LTL seem to reflect shifts in AD stage; they may have potential use as blood biomarkers to monitor disease onset and progression from MCI to AD.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/32289486; info:eu-repo/semantics/altIdentifier/wos/WOS:000538049900001; volume:136; numberofpages:7; journal:EXPERIMENTAL GERONTOLOGY; http://hdl.handle.net/11573/1392856Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85083208621

الإتاحة: https://doi.org/10.1016/j.exger.2020.110945Test
http://hdl.handle.net/11573/1392856Test

المؤلفون: Das L., Azmoon P., Banki M. A., Mantuano E., Gonias S. L.

المساهمون: Das, L., Azmoon, P., Banki, M. A., Mantuano, E., Gonias, S. L.

مصطلحات موضوعية: Animal, Cell Differentiation, Cytokine, Human, Inflammation, Inflammation Mediator, Lipopolysaccharide, Macrophage Colony-Stimulating Factor, Macrophage, Mice, Inbred C57BL, Neutralization Test, Nod1 Signaling Adaptor Protein, Nod2 Signaling Adaptor Protein, Receptors, N-Methyl-D-Aspartate, Tissue Plasminogen Activator, Toll-Like Receptors

الوصف: Tissue-type plasminogen activator (tPA) is a major activator of fibrinolysis, which also attenuates the pro-inflammatory activity of lipopolysaccharide (LPS) in bone marrow-derived macrophages (BMDMs) and in vivo in mice. The activity of tPA as an LPS response modifier is independent of its proteinase activity and instead, dependent on the N-methyl-D-aspartate Receptor (NMDA-R), which is expressed by BMDMs. The major Toll-like receptor (TLR) for LPS is TLR4. Herein, we show that enzymatically-inactive (EI) tPA blocks the response of mouse BMDMs to selective TLR2 and TLR9 agonists, rapidly reversing IκBα phosphorylation and inhibiting expression of TNFα, CCL2, interleukin-1β, and interleukin-6. The activity of EI-tPA was replicated by activated α2-macroglobulin, which like EI-tPA, signals through an NMDA-R-dependent pathway. EI-tPA failed to inhibit cytokine expression by BMDMs in response to agonists that target the Pattern Recognition Receptors (PRRs), NOD1 and NOD2, providing evidence for specificity in the function of EI-tPA. Macrophages isolated from the peritoneal space (PMs), without adding eliciting agents, expressed decreased levels of cell-surface NMDA-R compared with BMDMs. These cells were unresponsive to EI-tPA in the presence of LPS. However, when PMs were treated with CSF-1, the abundance of cell-surface NMDA-R increased and the ability of EI-tPA to neutralize the response to LPS was established. We conclude that the anti-inflammatory activity of EI-tPA is selective for TLRs but not all PRRs. The ability of macrophages to respond to EI-tPA depends on the availability of cell surface NMDA-R, which may be macrophage differentiation-state dependent.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/31697716; info:eu-repo/semantics/altIdentifier/wos/WOS:000530393800001; volume:14; issue:11; firstpage:e0224738; journal:PLOS ONE; http://hdl.handle.net/11573/1403164Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85074706382

الإتاحة: https://doi.org/10.1371/journal.pone.0224738Test
http://hdl.handle.net/11573/1403164Test

المؤلفون: Scarabino D, Veneziano L, Peconi M, Frontali M, Mantuano E, Corbo RM.

المساهمون: Scarabino, D, Veneziano, L, Peconi, M, Frontali, M, Mantuano, E, Corbo, Rm.

مصطلحات موضوعية: Biomarker, Huntington's disease development, Leukocyte telomere length, Neurodegenerative disease

الوصف: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. Though symptom onset commonly occurs at midlife and inversely correlates with the CAG repeat expansion, age at clinical onset and progression rate are variable. In the present study we investigated the relationship between leukocyte telomere length (LTL) and HD development. LTL was measured by real-time PCR in manifest HD patients (HD, n = 62), pre-manifest HD patients (pre-HD, n = 38), and age-matched controls (n = 76). Significant LTL differences were observed between the three groups (p < .0001), with LTL values in the order: HD < pre-HD < controls. The relationship between LTL and age was different in the three groups. An inverse relationship between mean LTL and CAG repeat number was found in the pre-HD (p = .03). The overall data seem to indicate that after age 30 years, LT begins to shorten markedly in pre-HD patients according to CAG number and increasing age, up to the values observed in HD. This very suggestive picture allowed us to hypothesize that in pre-manifest HD, LTL could be a measure of time to clinical HD onset. The possible use of LTL as a reliable biomarker to track HD development and progression was evaluated and discussed.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/30396032; info:eu-repo/semantics/altIdentifier/wos/WOS:000456639100006; volume:396; firstpage:25; lastpage:29; numberofpages:5; journal:JOURNAL OF THE NEUROLOGICAL SCIENCES; http://hdl.handle.net/11573/1235785Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85055905083

الإتاحة: https://doi.org/10.1016/j.jns.2018.10.024Test
http://hdl.handle.net/11573/1235785Test

المؤلفون: Zalfa C., Azmoon P., Mantuano E., Gonias S. L.

المساهمون: Zalfa, C., Azmoon, P., Mantuano, E., Gonias, S. L.

مصطلحات موضوعية: fibrinolysi, inflammation, NMDA receptor, plasmin, protease-activated receptor, tissue-type plasminogen activator

الوصف: Tissue-type plasminogen activator (tPA) activates fibrinolysis and also suppresses innate immune system responses to LPS in bone marrow-derived macrophages (BMDMs) and in vivo in mice. The objective of this study was to assess the activity of tPA as a regulator of macrophage physiology in the presence of plasmin. Enzymatically active and enzymatically inactive (EI) tPA appeared to comprehensively block the response to LPS in BMDMs, including expression of proinflammatory cytokines such as TNF-α and IL-1β and anti-inflammatory cytokines such as IL-10 and IL-1 receptor antagonist. The activity of EI-tPA as an LPS response modifier was conserved in the presence of plasminogen. By contrast, in BMDMs treated with tPA and plasminogen or preactivated plasmin, in the presence or absence of LPS, increased proinflammatory cytokine expression was observed and tPA failed to reverse the response. Plasmin independently activated NF-κB, ERK1/2, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase in BMDMs, which is characteristic of proinflammatory stimuli. Plasmin-induced cytokine expression was blocked by ε-aminocaproic acid, aprotinin, and inhibitors of the known plasmin substrate, Protease-activated receptor-1 (PAR-1), but not by N-methyl-d-aspartate receptor inhibitor, which blocks the effects of tPA on macrophages. Cytokine expression by BMDMs treated with the PAR-1 agonist, TFLLR, was not inhibited by EI-tPA, possibly explaining why EI-tPA does not inhibit macrophage responses to plasmin and providing evidence for specificity in the ability of tPA to oppose proinflammatory stimuli. Regulation of innate immunity by the fibrinolysis system may reflect the nature of the stimulus and a balance between the potentially opposing activities of tPA and plasmin.

العلاقة: info:eu-repo/semantics/altIdentifier/wos/WOS:000462155000010; volume:105; issue:4; firstpage:729; lastpage:740; numberofpages:12; journal:JOURNAL OF LEUKOCYTE BIOLOGY; http://hdl.handle.net/11573/1289622Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85060779124

الإتاحة: https://doi.org/10.1002/JLB.3A0818-329RRRTest
http://hdl.handle.net/11573/1289622Test

المؤلفون: PONTECORVI, PAOLA, Banki M. A., Zampieri C., Zalfa C., Azmoon P., Kounnas M. Z., Marchese C., Gonias S. L., Mantuano E.

المساهمون: Pontecorvi, Paola, Banki, M. A., Zampieri, C., Zalfa, C., Azmoon, P., Kounnas, M. Z., Marchese, C., Gonias, S. L., Mantuano, E.

مصطلحات موضوعية: Astrocyte, Inflammation, Microglia, Plasminogen, Protease-activated receptor, Tissue-type plasminogen activator, uPAR, Urokinase-type plasminogen activator, α-Enolase

الوصف: Background: Astrocytes contribute to the crosstalk that generates chronic neuro-inflammation in neurological diseases; however, compared with microglia, astrocytes respond to a more limited continuum of innate immune system stimulants. Recent studies suggest that the fibrinolysis system may regulate inflammation. The goal of this study was to test whether fibrinolysis system components activate astrocytes and if so, elucidate the responsible biochemical pathway. Methods: Primary cultures of astrocytes and microglia were prepared from neonatal mouse brains. The ability of purified fibrinolysis system proteins to elicit a pro-inflammatory response was determined by measuring expression of the mRNAs encoding tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and chemokine (C-C motif) ligand 2 (CCL2). IκBα phosphorylation also was measured. Plasminogen activation in association with cells was detected by chromogenic substrate hydrolysis. The activity of specific receptors was tested using neutralizing antibodies and reagents. Results: Astrocytes expressed pro-inflammatory cytokines when treated with plasminogen but not when treated with agonists for Toll-like Receptor-4 (TLR4), TLR2, or TLR9. Microglia also expressed pro-inflammatory cytokines in response to plasminogen; however, in these cells, the response was observed only when tissue-type plasminogen activator (tPA) was added to activate plasminogen. In astrocytes, endogenously produced urokinase-type plasminogen activator (uPA) converted plasminogen into plasmin in the absence of tPA. Plasminogen activation was dependent on the plasminogen receptor, α-enolase, and the uPA receptor, uPAR. Although uPAR is capable of directly activating cell-signaling, the receptor responsible for cytokine expression and IκBα phosphorylation response to plasmin was Protease-activated Receptor-1 (PAR-1). The pathway, by which plasminogen induced astrocyte activation, was blocked by inhibiting any one of the three receptors implicated in this pathway with reagents such as ...

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/31810478; info:eu-repo/semantics/altIdentifier/wos/WOS:000501815500002; volume:16; issue:1; firstpage:257; journal:JOURNAL OF NEUROINFLAMMATION; http://hdl.handle.net/11573/1342019Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85076163855

الإتاحة: https://doi.org/10.1186/s12974-019-1657-3Test
http://hdl.handle.net/11573/1342019Test

المؤلفون: Giunti, P, Mantuano, E, Frontali, M

المصدر: International Journal of Molecular Sciences , 21 (18) , Article 6472. (2020)

مصطلحات موضوعية: episodic ataxia, channelopathies, KCNA1, CACNA1A, SLC1A3, PRRT2, FGF14, SCN2A, SLCA1

الوصف: The term Episodic Ataxias (EA) was originally used for a few autosomal dominant diseases, characterized by attacks of cerebellar dysfunction of variable duration and frequency, often accompanied by other ictal and interictal signs. The original group subsequently grew to include other very rare EAs, frequently reported in single families, for some of which no responsible gene was found. The clinical spectrum of these diseases has been enormously amplified over time. In addition, episodes of ataxia have been described as phenotypic variants in the context of several different disorders. The whole group is somewhat confused, since a strong evidence linking the mutation to a given phenotype has not always been established. In this review we will collect and examine all instances of ataxia episodes reported so far, emphasizing those for which the pathophysiology and the clinical spectrum is best defined.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/10110040/1/ijms-21-06472.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10110040Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/10110040/1/ijms-21-06472.pdfTest
https://discovery.ucl.ac.uk/id/eprint/10110040Test/

المؤلفون: Iodice, A., Carecchio, M., Zorzi, G., Garavaglia, B., Spagnoli, C., Salerno, G.G., Frattini, D., Mencacci, N.E., Invernizzi, F., Veneziano, L., Mantuano, E., Angriman, M., Fusco, C.

المصدر: Brain and Development ; volume 41, issue 7, page 643 ; ISSN 0387-7604

مصطلحات موضوعية: Neurology (clinical), Developmental Neuroscience, General Medicine, Pediatrics, Perinatology and Child Health

الإتاحة: https://doi.org/10.1016/j.braindev.2019.04.011Test
https://api.elsevier.com/content/article/PII:S038776041930230X?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S038776041930230X?httpAccept=text/plainTest