Protective effects and mechanisms of Ndfipl on SH-SY5Y cell apoptosis in an in vitro Parkinson’s disease model

Li, Xing; Guo, Hua; Wang, D T; Sun, Lushi; Pan, Suyue

doi:10.4238/gmr.15026963

Cited by 8 publications

(4 citation statements)

References 13 publications

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“…Accompanied by an increased level of Ndfip1, the protein levels of both DMT1-IRE and DMT1-nonIRE are decreased dramatically. Our results are consistent with previous studies in PD models, Ndfip1 is decreased in 6-OHDA-treated rats and MES23.5 cells, whereas Ndfip1 overexpression leads to a decrease in DMT1 level in vitro (Howitt et al, 2014 ; Jia et al, 2015 ; Liu et al, 2015 ; Xing et al, 2016 ).…”

Section: Discussionsupporting

confidence: 93%

Lower Expression of Ndfip1 Is Associated With Alzheimer Disease Pathogenesis Through Decreasing DMT1 Degradation and Increasing Iron Influx

Tian

Zheng

et al. 2018

Front. Aging Neurosci.

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We have previously reported that high expression of divalent metal transporter 1 (DMT1) plays a crucial role in iron dyshomeostasis and β-amyloid (Aβ) peptide generation in the brain of Alzheimer’s disease (AD). Recent studies have shown that Nedd4 family interacting protein 1 (Ndfip1) can degrade DMT1 through ubiquitination pathway and reduce the accumulation of intracellular iron. The present study aims to evaluate whether Ndfip1 is involved in AD pathogenesis through mediating DMT1 degradation and iron metabolism. β-amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mouse and Ndfip1 transfected SH-SY5Y cells were used in this study. Immunohistochemistry and Western blot were performed to examine the distribution and expression levels of Ndfip1 and DMT1. In addition, ELISA and calcein fluorescence were carried out for analyzing the levels of Aβ peptide and iron influx, respectively. The results showed that Ndfip1 immunoreactivity was decreased in the cortex and hippocampus of APP/PS1 mice, compared with wild type (WT) controls. Colocalization of Ndfip1 and Aβ within senile plaques could be observed. Immunoblot analyses showed that low expression of Ndfip1 and high expression of DMT1 proteins were detected in APP/PS1 mouse brain, compared with age-matched WT animals. Overexpression of Ndfip1 down-regulated DMT1 expression, and reduced iron influx and Aβ secretion in SH-SY5Y cells. Further, overexpressed Ndfip1 significantly attenuated iron-induced cell damage in Ndfip1 transfected cells. The present study suggests that lower expression of Ndfip1 might be associated with the pathogenesis of AD, through decreasing DMT1 degradation and increasing iron accumulation in the brain.

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Section: Discussionsupporting

confidence: 93%

Lower Expression of Ndfip1 Is Associated With Alzheimer Disease Pathogenesis Through Decreasing DMT1 Degradation and Increasing Iron Influx

Tian

Zheng

et al. 2018

Front. Aging Neurosci.

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“…Data are mean ± SEM of at least three independent experimental runs, with samples collected from multiple passages of cells. * P < .05; * * P < .01. role in neuronal development [18 , 19] and its importance in neurodegeneration has been increasingly documented in the literature [20][21][22][23][24][25] . Our findings showed that Nedd4-1 increased in both human AD patient and J20 mouse (age-dependently) hippocampus, which is similar to previous findings in neurodegenerative conditions [25] .…”

Section: Discussionmentioning

confidence: 99%

“…Both Nedd4-1 and Nedd4-2 are involved in the ubiquitination of several mammalian transporters in various cellular systems [12][13][14][15][16][17] . Further, Nedd4-1 plays a crucial role in neuronal development [18 , 19] and its importance in neurodegeneration has been recognized in recent years [20][21][22][23][24][25] . A classical Nedd4 protein interacting motif ("PPXY") allows specified association with protein substrates [14 , 26] .…”

Section: Introductionmentioning

confidence: 99%

Regulation of human sodium-dependent vitamin C transporter-2 function in neuronal cells by ubiquitin E3 ligase Nedd4-1

Subramanian

Teafatiller²,

Kitazawa³

et al. 2023

Physiology

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The ubiquitin pathway regulates the functional expression of several transporters in many cellular systems. However, currently, nothing is known about the role of ubiquitination E3 ligase, neural precursor cell expressed developmentally down-regulated gene 4 (Nedd4-1) in regulating human vitamin C transporter-2 (hSVCT2, the product of the SLC23A2 gene) in neuronal cells. Nedd4-1 has been identified as a putative interactor with hSVCT2 and in the brain, hSVCT2 is predominantly expressed and mediates the cellular uptake of ascorbic acid (AA). Our aim in this investigation was to address this issue using in vitro (SH-SY5Y and HEK-293 cells), and in vivo (mouse) models, together with an array of physiological, cellular and molecular biological approaches. The results showed that the expression of Nedd4-1 in neuronal samples (human and mouse hippocampi and SH-SY5Y cells) is markedly higher than that of Nedd4-2. Interestingly, Nedd4-1 expression was shown to be significantly higher in the hippocampi of patients with Alzheimer’s disease (AD) and a J20 mouse model of AD. In addition, Nedd4-1-GFP and hSVCT2-DsRed co-localized in intracellular vesicles and at the cell membrane in HEK-293 cells. Further, the co-expression of Nedd4-1 with hSVCT2 showed a marked decrease in AA uptake. In contrast, Nedd4-1 siRNA knockdown significantly increased the AA uptake. Further, we have mutated a classical Nedd4 protein interacting motif (‘PPXY’) within the hSVCT2 polypeptide and observed significantly reduced AA uptake due to the intracellular retention of the hSVCT2 mutant compared to hSVCT2 wild-type. Collectively, our data demonstrate that Nedd4-1 dependent ubiquitination regulates hSVCT2 functional expression in neuronal cells. Supported by NIH grant DK 107474 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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“…NEDD4-1 also interacts with NDFIP1 (NEDD4 family interacting protein), a trans-membrane protein with a protective role in a cell model of PD, helping reduce apoptosis and improving cell survival rate. This binding generates enhanced expression of NDFIP1 [ 108 ]. Loss of NEDD4-1 has been associated with elevation of RTP801, a pro-apoptotic protein sufficient and necessary to induce neuronal death in cellular and animal models of PD [ 109 ].…”

Section: Nedd4 E3 Ligases In Neurodegenerationmentioning

confidence: 99%

The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration

Haouari

Vourc’h

Jeanne

et al. 2022

IJMS

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The ubiquitin pathway regulates the function of many proteins and controls cellular protein homeostasis. In recent years, it has attracted great interest in neurodevelopmental and neurodegenerative diseases. Here, we have presented the first review on the roles of the 9 proteins of the HECT E3 ligase NEDD4 subfamily in the development and function of neurons and the central nervous system (CNS). We discussed their regulation and their direct or indirect involvement in neurodevelopmental diseases, such as intellectual disability, and neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease or Amyotrophic Lateral Sclerosis. Further studies on the roles of these proteins, their regulation and their targets in neurons will certainly contribute to a better understanding of neuronal function and dysfunction, and will also provide interesting information for the development of therapeutics targeting them.

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Protective effects and mechanisms of Ndfipl on SH-SY5Y cell apoptosis in an in vitro Parkinson’s disease model

Cited by 8 publications

References 13 publications

Lower Expression of Ndfip1 Is Associated With Alzheimer Disease Pathogenesis Through Decreasing DMT1 Degradation and Increasing Iron Influx

Lower Expression of Ndfip1 Is Associated With Alzheimer Disease Pathogenesis Through Decreasing DMT1 Degradation and Increasing Iron Influx

Regulation of human sodium-dependent vitamin C transporter-2 function in neuronal cells by ubiquitin E3 ligase Nedd4-1

The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration

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