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1

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Ncx3-Induced Mitochondrial Dysfunction in Midbrain Leads to Neuroinflammation in Striatum of A53t-α-Synuclein Transgenic Old Mice

Di Martino, Rossana ; Sisalli, Maria ; Sirabella, Rossana ; [et al.]

MDPI AG ; 2021

In: International Journal of Molecular Sciences Vol. 22, No. 15 ( 2021-07-30), p. 8177-

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In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 15 ( 2021-07-30), p. 8177-

Abstract: The exact mechanism underlying selective dopaminergic neurodegeneration is not completely understood. The complex interplay among toxic alpha-synuclein aggregates, oxidative stress, altered intracellular Ca2+-homeostasis, mitochondrial dysfunction and disruption of mitochondrial integrity is considered among the pathogenic mechanisms leading to dopaminergic neuronal loss. We herein investigated the molecular mechanisms leading to mitochondrial dysfunction and its relationship with activation of the neuroinflammatory process occurring in Parkinson’s disease. To address these issues, experiments were performed in vitro and in vivo in mice carrying the human mutation of α-synuclein A53T under the prion murine promoter. In these models, the expression and activity of NCX isoforms, a family of important transporters regulating ionic homeostasis in mammalian cells working in a bidirectional way, were evaluated in neurons and glial cells. Mitochondrial function was monitored with confocal microscopy and fluorescent dyes to measure mitochondrial calcium content and mitochondrial membrane potential. Parallel experiments were performed in 4 and 16-month-old A53T-α-synuclein Tg mice to correlate the functional data obtained in vitro with mitochondrial dysfunction and neuroinflammation through biochemical analysis. The results obtained demonstrated: 1. in A53T mice mitochondrial dysfunction occurs early in midbrain and later in striatum; 2. mitochondrial dysfunction occurring in the midbrain is mediated by the impairment of NCX3 protein expression in neurons and astrocytes; 3. mitochondrial dysfunction occurring early in midbrain triggers neuroinflammation later into the striatum, thus contributing to PD progression during mice aging.

Type of Medium: Online Resource

ISSN: 1422-0067

URL: Article

DOI: 10.3390/ijms22158177

Language: English

Publisher: MDPI AG

Publication Date: 2021

detail.hit.zdb_id: 2019364-6

SSG: 12

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2

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nNOS and p-ERK involvement in the neuroprotection exerted by remote postconditioning in rats subjected to transient middle cerebral artery occlusion

Pignataro, Giuseppe ; Esposito, Elga ; Sirabella, Rossana ; [et al.]

Elsevier BV ; 2013

In: Neurobiology of Disease Vol. 54 ( 2013-06), p. 105-114

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In: Neurobiology of Disease, Elsevier BV, Vol. 54 ( 2013-06), p. 105-114

Type of Medium: Online Resource

ISSN: 0969-9961

URL: Article

DOI: 10.1016/j.nbd.2013.02.008

Language: English

Publisher: Elsevier BV

Publication Date: 2013

detail.hit.zdb_id: 1471408-5

SSG: 12

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3

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Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+ exchanger 3 downregulation

Anzilotti, Serenella ; Brancaccio, Paola ; Simeone, Giuseppe ; [et al.]

Springer Science and Business Media LLC ; 2018

In: Cell Death & Disease Vol. 9, No. 2 ( 2018-02-12)

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In: Cell Death & Disease, Springer Science and Business Media LLC, Vol. 9, No. 2 ( 2018-02-12)

Abstract: Preconditioning (PC) is a phenomenon wherein a mild insult induces resistance to a later, severe injury. Although PC has been extensively studied in several neurological disorders, no studies have been performed in amyotrophic lateral sclerosis (ALS). Here we hypothesize that a sub-toxic acute exposure to the cycad neurotoxin beta-methylamino-L-alanine (L-BMAA) is able to delay ALS progression in SOD1 G93A mice and that NCX3, a membrane transporter able to handle the deregulation of ionic homeostasis occurring during ALS, takes part to this neuroprotective effect. Preconditioning effect was examined on disease onset and duration, motor functions, and motor neurons in terms of functional declines and severity of histological damage in male and female mice. Our findings demonstrate that a sub-toxic dose of L-BMAA works as preconditioning stimulus and is able to delay ALS onset and to prolong ALS mice survival. Interestingly, preconditioning prevented NCX3 downregulation in SOD1 G93A mice spinal cord, leading to an increased number of motor neurons associated to a reduced astrogliosis, and reduced the denervation of neuromuscular junctions observed in SOD1 G93A mice. These protective effects were mitigated in ncx3+/− mice. This study established for the first time an animal model of preconditioning in ALS and candidates NCX3 as a new therapeutic target.

Type of Medium: Online Resource

ISSN: 2041-4889

URL: Article

DOI: 10.1038/s41419-017-0227-9

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2018

detail.hit.zdb_id: 2541626-1

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4

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An increase in Semaphorin 3A biases the axonal direction and induces an aberrant dendritic arborization in an in vitro model of human neural progenitor differentiation

Ferretti, Gabriella ; Romano, Alessia ; Sirabella, Rossana ; [et al.]

Springer Science and Business Media LLC ; 2022

In: Cell & Bioscience Vol. 12, No. 1 ( 2022-11-08)

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In: Cell & Bioscience, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2022-11-08)

Abstract: Semaphorins (Sema) belong to a large family of repellent guidance cues instrumental in guiding axons during development. In particular, Class 3 Sema (Sema 3) is among the best characterized Sema family members and the only produced as secreted proteins in mammals, thereby exerting both autocrine and paracrine functions. Intriguingly, an increasing number of studies supports the crucial role of the Sema 3A in hippocampal and cortical neurodevelopment. This means that alterations in Sema 3A signaling might compromise hippocampal and cortical circuits and predispose to disorders such as autism and schizophrenia. Consistently, increased Sema 3A levels have been detected in brain of patients with schizophrenia and many polymorphisms in Sema 3A or in the Sema 3A receptors, Neuropilins (Npn 1 and 2) and Plexin As (Plxn As), have been associated to autism. Results Here we present data indicating that when overexpressed, Sema 3A causes human neural progenitors (NP) axonal retraction and an aberrant dendritic arborization. Similarly, Sema 3A, when overexpressed in human microglia, triggers proinflammatory processes that are highly detrimental to themselves as well as NP. Indeed, NP incubated in microglia overexpressing Sema 3A media retract axons within an hour and then start suffering and finally die. Sema 3A mediated retraction appears to be related to its binding to Npn 1 and Plxn A2 receptors, thus activating the downstream Fyn tyrosine kinase pathway that promotes the threonine-serine kinase cyclin-dependent kinase 5, CDK5, phosphorylation at the Tyr15 residue and the CDK5 processing to generate the active fragment p35. Conclusions All together this study identifies Sema 3A as a critical regulator of human NP differentiation. This may imply that an insult due to Sema 3A overexpression during the early phases of neuronal development might compromise neuronal organization and connectivity and make neurons perhaps more vulnerable to other insults across their lifespan.

Type of Medium: Online Resource

ISSN: 2045-3701

URL: Article

DOI: 10.1186/s13578-022-00916-1

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2593367-X

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5

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Mesoangioblasts at 20: From the embryonic aorta to the patient bed

Cossu, Giulio ; Tonlorenzi, Rossana ; Brunelli, Silvia ; [et al.]

Frontiers Media SA ; 2023

In: Frontiers in Genetics Vol. 13 ( 2023-1-4)

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In: Frontiers in Genetics, Frontiers Media SA, Vol. 13 ( 2023-1-4)

Abstract: In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had accumulated that during muscle development and regeneration things may be more complex than a simple sequence of binary choices (e.g., dorsal vs. ventral somite). LacZ expressing fibroblasts could fuse with unlabelled myoblasts but not among themselves or with other cell types. Bone marrow derived, circulating progenitors were able to participate in muscle regeneration, though in very small percentage. Searching for the embryonic origin of these progenitors, we identified them as originating at least in part from the embryonic aorta and, at later stages, from the microvasculature of skeletal muscle. While continuing to investigate origin and fate of MABs, the fact that they could be expanded in vitro (also from human muscle) and cross the vessel wall, suggested a protocol for the cell therapy of muscular dystrophies. We tested this protocol in mice and dogs before proceeding to the first clinical trial on Duchenne Muscular Dystrophy patients that showed safety but minimal efficacy. In the last years, we have worked to overcome the problem of low engraftment and tried to understand their role as auxiliary myogenic progenitors during development and regeneration.

Type of Medium: Online Resource

ISSN: 1664-8021

URL: Article

DOI: 10.3389/fgene.2022.1056114

Language: Unknown

Publisher: Frontiers Media SA

Publication Date: 2023

detail.hit.zdb_id: 2606823-0

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6

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Targeted Disruption of Na + /Ca 2+ Exchanger 3 (NCX3) Gene Leads to a Worsening of Ischemic Brain Damage

Molinaro, Pasquale ; Cuomo, Ornella ; Pignataro, Giuseppe ; [et al.]

Society for Neuroscience ; 2008

In: The Journal of Neuroscience Vol. 28, No. 5 ( 2008-01-30), p. 1179-1184

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In: The Journal of Neuroscience, Society for Neuroscience, Vol. 28, No. 5 ( 2008-01-30), p. 1179-1184

Abstract: Na + /Ca 2+ exchanger 3 (NCX3), one of the three isoforms of the NCX family, is highly expressed in the brain and is involved in the maintenance of intracellular Na + and Ca 2+ homeostasis. Interestingly, whereas the function of NCX3 under physiological conditions has been determined, its role under anoxia is still unknown. To assess NCX3 role in cerebral ischemia, we exposed ncx3−/− mice to transient middle cerebral artery occlusion followed by reperfusion. In addition, to evaluate the effect of ncx3 ablation on neuronal survival, organotypic hippocampal cultures and primary cortical neurons from ncx3−/− mice were subjected to oxygen glucose deprivation (OGD) plus reoxygenation. Here we report that ncx3 gene suppression leads to a worsening of brain damage after focal ischemia and to a massive neuronal death in all the hippocampal fields of organotypic cultures as well as in cortical neurons from ncx3−/− mice exposed to OGD plus reoxygenation. In addition, in ncx3−/− cortical neurons exposed to hypoxia, NCX currents, recorded in the reverse mode of operation, were significantly lower than those detected in ncx3+/+. From these results, NCX3 protein emerges as a new molecular target that may have a potential therapeutic value in modulating cerebral ischemia.

Type of Medium: Online Resource

ISSN: 0270-6474 , 1529-2401

URL: Article

DOI: 10.1523/JNEUROSCI.4671-07.2008

Language: English

Publisher: Society for Neuroscience

Publication Date: 2008

detail.hit.zdb_id: 1475274-8

SSG: 12

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7

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NCX1 Exchanger Cooperates with Calretinin to Confer Preconditioning-Induced Tolerance Against Cerebral Ischemia in the Striatum

Boscia, Francesca ; Casamassa, Antonella ; Secondo, Agnese ; [et al.]

Springer Science and Business Media LLC ; 2016

In: Molecular Neurobiology Vol. 53, No. 2 ( 2016-3), p. 1365-1376

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In: Molecular Neurobiology, Springer Science and Business Media LLC, Vol. 53, No. 2 ( 2016-3), p. 1365-1376

Type of Medium: Online Resource

ISSN: 0893-7648 , 1559-1182

URL: Article

DOI: 10.1007/s12035-015-9095-4

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2016

detail.hit.zdb_id: 2079384-4

SSG: 12

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8

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BHK cells transfected with NCX3 are more resistant to hypoxia followed by reoxygenation than those transfected with NCX1 and NCX2: Possible relationship with mitochondrial membrane potential

Secondo, Agnese ; Staiano, Rosaria Ilaria ; Scorziello, Antonella ; [et al.]

Elsevier BV ; 2007

In: Cell Calcium Vol. 42, No. 6 ( 2007-12), p. 521-535

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In: Cell Calcium, Elsevier BV, Vol. 42, No. 6 ( 2007-12), p. 521-535

Type of Medium: Online Resource

ISSN: 0143-4160

URL: Article

DOI: 10.1016/j.ceca.2007.01.006

Language: English

Publisher: Elsevier BV

Publication Date: 2007

detail.hit.zdb_id: 2002623-7

SSG: 12

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Involvement of the Na+/Ca2+ exchanger isoform 1 (NCX1) in Neuronal Growth Factor (NGF)-induced Neuronal Differentiation through Ca2+-dependent Akt Phosphorylation

Secondo, Agnese ; Esposito, Alba ; Sirabella, Rossana ; [et al.]

Elsevier BV ; 2015

In: Journal of Biological Chemistry Vol. 290, No. 3 ( 2015-01), p. 1319-1331

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In: Journal of Biological Chemistry, Elsevier BV, Vol. 290, No. 3 ( 2015-01), p. 1319-1331

Type of Medium: Online Resource

ISSN: 0021-9258

URL: Article

DOI: 10.1074/jbc.M114.555516

Language: English

Publisher: Elsevier BV

Publication Date: 2015

detail.hit.zdb_id: 2141744-1

detail.hit.zdb_id: 1474604-9

SSG: 12

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Ca2+-independent caspase-3 but not Ca2+-dependent caspase-2 activation induced by oxidative stress leads to SH-SY5Y human neuroblastoma cell apoptosis

Amoroso, Salvatore ; D'Alessio, Angela ; Sirabella, Rossana ; [et al.]

Wiley ; 2002

In: Journal of Neuroscience Research Vol. 68, No. 4 ( 2002-05-15), p. 454-462

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In: Journal of Neuroscience Research, Wiley, Vol. 68, No. 4 ( 2002-05-15), p. 454-462

Type of Medium: Online Resource

ISSN: 0360-4012 , 1097-4547

URL: Issue

URL: Journal

URL: Article

DOI: 10.1002/jnr.v68:4

DOI: 10.1002/(ISSN)1097-4547

DOI: 10.1002/jnr.10199

Language: English

Publisher: Wiley

Publication Date: 2002

detail.hit.zdb_id: 1474904-X

SSG: 12

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Kooperativer Bibliotheksverbund

Berlin Brandenburg