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      Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients

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          Abstract

          Spinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene ( SMN1) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense oligonucleotide nusinersen has recently improved the natural course of this disease. Here, we investigated, with a functional proteomic approach, cerebrospinal fluid (CSF) protein profiles from SMA type 1 patients who underwent nusinersen administration to clarify the biochemical response to the treatment and to monitor disease progression based on therapy. Six months after starting treatment (12 mg/5 mL × four doses of loading regimen administered at days 0, 14, 28, and 63), we observed a generalized reversion trend of the CSF protein pattern from our patient cohort to that of control donors. Notably, a marked up-regulation of apolipoprotein A1 and apolipoprotein E and a consistent variation in transthyretin proteoform occurrence were detected. Since these multifunctional proteins are critically active in biomolecular processes aberrant in SMA, i.e., synaptogenesis and neurite growth, neuronal survival and plasticity, inflammation, and oxidative stress control, their nusinersen induced modulation may support SMN improved-expression effects. Hence, these lipoproteins and transthyretin could represent valuable biomarkers to assess patient responsiveness and disease progression.

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          Most cited references139

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          Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4

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            REVIGO Summarizes and Visualizes Long Lists of Gene Ontology Terms

            Outcomes of high-throughput biological experiments are typically interpreted by statistical testing for enriched gene functional categories defined by the Gene Ontology (GO). The resulting lists of GO terms may be large and highly redundant, and thus difficult to interpret. REVIGO is a Web server that summarizes long, unintelligible lists of GO terms by finding a representative subset of the terms using a simple clustering algorithm that relies on semantic similarity measures. Furthermore, REVIGO visualizes this non-redundant GO term set in multiple ways to assist in interpretation: multidimensional scaling and graph-based visualizations accurately render the subdivisions and the semantic relationships in the data, while treemaps and tag clouds are also offered as alternative views. REVIGO is freely available at http://revigo.irb.hr/.
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              ROS function in redox signaling and oxidative stress.

              Oxidative stress refers to elevated intracellular levels of reactive oxygen species (ROS) that cause damage to lipids, proteins and DNA. Oxidative stress has been linked to a myriad of pathologies. However, elevated ROS also act as signaling molecules in the maintenance of physiological functions--a process termed redox biology. In this review we discuss the two faces of ROS--redox biology and oxidative stress--and their contribution to both physiological and pathological conditions. Redox biology involves a small increase in ROS levels that activates signaling pathways to initiate biological processes, while oxidative stress denotes high levels of ROS that result in damage to DNA, protein or lipids. Thus, the response to ROS displays hormesis, given that the opposite effect is observed at low levels compared with that seen at high levels. Here, we argue that redox biology, rather than oxidative stress, underlies physiological and pathological conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                21 April 2021
                May 2021
                : 22
                : 9
                : 4329
                Affiliations
                [1 ]Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, 53100 Siena, Italy; laura.bianchi@ 123456unisi.it (L.B.); lorenz.vantaggiato@ 123456gmail.com (L.V.); luca.bini@ 123456unisi.it (L.B.)
                [2 ]Nemo Sud Clinical Centre, 98125 Messina, Italy; mariasframeli@ 123456hotmail.it (M.S.); gianlucav.ta81@ 123456gmail.com (G.L.V.)
                [3 ]Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; aciranni@ 123456unime.it (A.C.); francesca.polito@ 123456unime.it (F.P.); roteri@ 123456unime.it (R.O.); smessina@ 123456unime.it (S.M.); aguenoz@ 123456unime.it (M.A.)
                [4 ]Neonatal and Paediatric Intensive Care Unit, Department of Human Pathology in Adult and Developmental Age, University of Messina, 98125 Messina, Italy; egitto@ 123456unime.it
                [5 ]Dentistry and Biotechnology, and Proteomics Unit, Centre of Advanced Studies and Technoloy, Department Medical, Oral & Biotechnological Sciences, “G. d’Annunzio”, University of Chieti-Pescara, 66100 Chieti, Italy; f.digiuseppe@ 123456unich.it (F.D.G.); stefania.angelucci@ 123456unich.it (S.A.)
                [6 ]Intensive Care Unit, AOU Policlinico “G. Martino”, 98125 Messina, Italy; anversaci@ 123456unime.it
                Author notes
                [* ]Correspondence: vitag@ 123456unime.it
                [†]

                These Authors shared first authorship.

                [‡]

                Luca Bini and M’hammed Aguennouz have been acting as senior investigators and should be considered equal last Authors.

                Author information
                https://orcid.org/0000-0001-7994-3391
                https://orcid.org/0000-0001-8951-2106
                https://orcid.org/0000-0003-0440-0354
                Article
                ijms-22-04329
                10.3390/ijms22094329
                8122268
                33919289
                e9924722-c0e5-4be9-b088-23be7192a132
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 01 April 2021
                : 19 April 2021
                Categories
                Article

                Molecular biology
                neuromuscular disease,spinal muscular atrophy type 1,nusinersen,aso,apolipoprotein a1,apolipoprotein e,transthyretin,haptoglobin,carbonyl groups,oxidized proteins,survival motor neuron (smn)

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