Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt

Molinaro, Pasquale; Sirabella, Rossana; Pignataro, Giuseppe; Petrozziello, Tiziana; Secondo, Agnese; Boscia, Francesca; Vinciguerra, Antonio; Cuomo, Ornella; Philipson, Kenneth D.; Felice, Mario De; Lauro, Roberto Di; Renzo, Gianfranco Di; Annunziato, Lucio

doi:10.1177/0271678x15611913

Cited by 35 publications

(22 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the increased NCX3 expression induced by PC is partially prevented in ncx3+/− mice, this is sufficient to prevent PC-induced protection. The fact that NCX3 may represent one of the effector of ALS PC is in line with previous works demonstrating that the genetic ablation of this transporter worsens the course of several neurological disorders such as brain ischemia, multiple sclerosis, Alzheimer disease and epilepsy 12 , 13 .…”

Section: Discussionsupporting

confidence: 88%

“…Protein content was determined by the Bradford method 38 . Percoll-purified synaptosomes were resuspended in medium B (1 mg/ml) and loaded with the ratiometric fluorescent Ca 2+ indicator Fura-2 AM (6 µM) 12 in the presence of 16 µM bovine serum albumin for 45 min at 37 °C. Dye-loaded synaptosomes were then washed by centrifugation, resuspended in medium B containing 1.2 mM CaCl 2 , and attached to poly- d -lysine-coated coverslips for 20 min at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Anzilotti

Brancaccio²,

Simeone³

et al. 2018

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

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

Anzilotti

Brancaccio²,

Simeone³

et al. 2018

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…An investigator blinded to group and treatment tested the mice on days 1, 7, 14, 21, and 28 after surgery. The mNSS measures motor function, gait, sensory function, balance, and reflex in a series of tests, each with its own scoring range[51]. Mice are given a score of 0 for normal function and a maximum score for no response or inability to perform the task.…”

Section: Methodsmentioning

confidence: 99%

Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone

Wang

et al. 2017

Transl. Stroke Res.

View full text Add to dashboard Cite

Choline acetyltransferase-positive (ChAT+) neurons within the subventricular zone (SVZ) have been shown to promote neurogenesis after stroke in mice by secreting acetylcholine (ACh); however, the mechanisms remain unclear. Receptors known to bind ACh include the nicotinic ACh receptors (nAChRs), which are present in the SVZ and have been shown to be important for cell proliferation, differentiation, and survival. In this study, we investigated the neurogenic role of the α7 nAChR in a mouse model of middle cerebral artery occlusion (MCAO) by using α7 nAChR inhibitor methyllycaconitine. Mice subjected to MCAO exhibited elevated expression of cytomembrane and nuclear fibroblast growth factor receptor 1 (FGFR1), as well as increased expression of PI3K, pAkt, doublecortin (DCX), polysialylated neuronal cell adhesion molecule (PSA-NCAM), and mammalian achaete-scute homolog 1 (Mash1). MCAO mice also had more GFAP/BrdU-positive cells and DCX-positive cells in the SVZ than did the sham-operated group. Methyllycaconitine treatment increased cytomembrane FGFR1 expression and GFAP/BrdU-positive cells, upregulated the levels of PI3K and pAkt, decreased nuclear FGFR1 expression, decreased the number of DCX-positive cells, and reduced the levels of DCX, PSA-NCAM, and Mash1 in the SVZ of MCAO mice compared with levels in vehicle-treated MCAO mice. MCAO mice treated with α7 nAChR agonist PNU-282987 exhibited the opposite effects. Our data show that α7 nAChR may decrease the proliferation of neural stem cells and promote differentiation of existing neural stem cells after stroke. These results identify a new mechanism of SVZ ChAT+ neuron-induced neurogenesis.

show abstract

“…This effect on nucleoplasmic Ca 2+ was due to the selective localization of XIP-NLS in the nucleus where it binded to the f-loop of nuNCX1, as also demonstrated by the coimmunoprecipitation between the peptide and nuNCX1 in isolated nuclei. Accordingly, the same interaction occurs at plasma membrane NCX level 22 . Interestingly, XIP-NLS inhibited nuNCX1 Ca 2+ n -extruding function without affecting the activity of plasma membrane NCX1, as demonstrated by patch-clamp experiments in whole neuronal cells.…”

Section: Discussionmentioning

confidence: 76%

“…In addition, outer and inner membranes of NE are provided with K + , Cl − , and R-type Ca 2+ channels 13 – 15 , Na + /H + exchanger 1 16 , Ca 2+ -ATPase pump 17 , and NCX1 18 , 19 . Despite the existent knowledge on the role of plasma membrane NCX in the regulation of intracellular Ca 2+ concentrations and Ca 2+ -dependent pathways 20 – 22 , nuNCX1 function remains unexplored. Interestingly, global silencing of NCX1 prevents neurite outgrowth through the inhibition of Akt pathway thus reducing NeuN-positive neurons 23 .…”

Section: Introductionmentioning

confidence: 99%

Na+/Ca2+ exchanger 1 on nuclear envelope controls PTEN/Akt pathway via nucleoplasmic Ca2+ regulation during neuronal differentiation

et al. 2018

Self Cite

View full text Add to dashboard Cite

Nuclear envelope (NE) is a Ca2+-storing organelle controlling neuronal differentiation through nuclear Ca2+ concentrations ([Ca2+]n). However, how [Ca2+]n regulates this important function remains unknown. Here, we investigated the role of the nuclear form of the Na+/Ca2+ exchanger 1(nuNCX1) during the different stages of neuronal differentiation and the involvement of PTEN/PI3’K/Akt pathway. In neuronal cells, nuNCX1 was detected on the inner membrane of the NE where protein expression and activity of the exchanger increased during NGF-induced differentiation. nuNCX1 activation by Na+-free perfusion induced a time-dependent activation of nuclear-resident PI3K/Akt pathway in isolated nuclei. To discriminate the contribution of nuNCX1 from those of plasma membrane NCX, we generated a chimeric protein composed of the fluorophore EYFP, the exchanger inhibitory peptide, and the nuclear localization signal, named XIP-NLS. Fura-2 measurements on single nuclei and patch-clamp experiments in whole-cell configuration showed that XIP-NLS selectively inhibited nuNCX1. Once it reached the nuclear compartment, XIP-NLS increased the nucleoplasmic Ca2+ peak elicited by ATP and reduced Akt phosphorylation, GAP-43 and MAP-2 expression through nuclear-resident PTEN induction. Furthermore, in accordance with the prevention of the neuronal phenotype, XIP-NLS significantly reduced TTX-sensitive Na+ currents and membrane potential during neuronal differentiation. The selective inhibition of nuNCX1 by XIP-NLS increased the percentage of β III tubulin-positive immature neurons in mature cultures of MAP-2-positive cortical neurons, thus unraveling a new function for nuNCX1 in regulating neuronal differentiation through [Ca2+]n-dependent PTEN/PI3K/Akt pathway.

show abstract

Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt

Cited by 35 publications

References 51 publications

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

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

Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone

Na+/Ca2+ exchanger 1 on nuclear envelope controls PTEN/Akt pathway via nucleoplasmic Ca2+ regulation during neuronal differentiation

Contact Info

Product

Resources

About