Necroptosis-like Neuronal Cell Death Caused by Cellular Cholesterol Accumulation

Funakoshi, Takeshi; Aki, Toshihiko; Tajiri, Masateru; Unuma, Kana; Uemura, Kenichiro

doi:10.1074/jbc.m116.727404

Cited by 22 publications

(20 citation statements)

References 48 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, amine-modified polystyrene nanoparticles accumulate in lysosome, and induce LMP, resulting in induction of cell death [ 40 ]. In addition, l -norephedrine, a sympathomimetic amine, induces intracellular cholesterol accumulation in lysosome, and increases lysosomal vacuolization [ 41 ]. Yuan et al reported that accumulation of cholesterol oxidation products in lysosome induces vacuolization and increases lysosomal damages, which plays a critical role in cell death in macrophage [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells

Min

Kwon

2020

Cancers

View full text Add to dashboard Cite

FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, is a synthetic compound produced by the modification of a metabolite from I. sinclairii. Here, we found that FTY720 induced non-apoptotic cell death in human glioma cells (U251MG, U87MG, and U118MG). FTY720 (10 µM) dramatically induced cytoplasmic vacuolation in glioma cells. However, FTY720-mediated vacuolation and cell death are not associated with autophagy. Genetic or pharmacological inhibition of autophagy did not inhibit FTY720-induced cell death. Herein, we detected that FTY720-induced cytoplasmic vacuoles were stained with lysotracker red, and FTY720 induced lysosomal membrane permeabilization (LMP). Interestingly, cathepsin inhibitors (E64D and pepstatin A) and ectopic expression of heat shock protein 70 (HSP70), which is an endogenous inhibitor of LMP, markedly inhibited FTY720-induced cell death. Our results demonstrated that FTY720 induced non-apoptotic cell death via the induction of LMP in human glioma cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells

Min

Kwon

2020

Cancers

View full text Add to dashboard Cite

show abstract

“…We note also that this feedback would operate when cholesterol increases due to enhanced synthesis. It should not be functional in conditions of defective extrusion (Djelti et al., ) or dysfunctional lysosomal storage (Funakoshi, Aki, Tajiri, Unuma, & Uemura, ).…”

Section: Discussionmentioning

confidence: 99%

Lipid markers and related transcripts during excitotoxic neurodegeneration in kainate‐treated mice

Chali

Milior

Marty

et al. 2019

Eur J of Neuroscience

View full text Add to dashboard Cite

Lipid homeostasis is dysregulated in some neurodegenerative diseases and after brain injuries due to excess glutamate or lack of oxygen. However the kinetics and cell specificity of dysregulation in different groups of lipids during excitotoxic neuronal death are not clear. Here we examined the changes during excitotoxic neuronal death induced by injecting kainic acid (KA) into the CA1 region of mouse hippocampus. We compared neuronal loss and glial cell proliferation with changes in lipid‐related transcripts and markers for different lipid groups, over 12 days after KA‐treatment. As neurons showed initial signs of damage, transcripts and proteins linked to fatty acid oxidation were up‐regulated. Cholesterol biosynthesis induced by transcripts controlled by the transcription factor Srebp2 seems to be responsible for a transient increase in neuronal free cholesterol at 1 to 2 days. In microglia, but not in neurons, Perilipin‐2 associated lipid droplets were induced and properties of Nile red emissions suggest lipid contents change over time. After microglial expression of phagocytotic markers at 2 days, some neutral lipid deposits co‐localized with lysosome markers of microglia and were detected within putative phagocytotic cups. These data delineate distinct lipid signals in neurons and glial cells during excitotoxic processes from initial neuronal damage to engagement of the lysosome–phagosome system.

show abstract

“…The neuroprotective potential of Nec-1 and its analogs in cellular and animal models of ischemia is rather well supported (Chavez-Valdez et al 2012Degterev et al 2005;Li et al 2018;Ni et al 2018;Northington et al 2011;Xu et al 2010a;Yang et al 2017a;Yin et al 2015;Zhan et al 2019;Zhang et al 2016). Moreover, in an in vitro setting, Nec-1 attenuated the neuronal cell damage induced by various harmful agents, e.g., oaubain, glutamate (Glu), N-methyl-D-aspartate (NMDA), 6hydroxydopamine (6-OHDA), rotenone, 1-methyl-4phenylpyridinium ion (MPP+), methamphetamine, aluminum (Al), 24(S)-hydroxycholesterol, cholesterol, staurosporine, and doxorubicin (Funakoshi et al 2016;Ito et al 2017;Jantas et al 2014a;Li et al 2011;Wang et al 2014;Wu et al 2015;Xiong et al 2016;Xu et al 2007;Yamanaka et al 2011;Zhang et al 2013). It should be noted that the protective effect of Nec-1 in the above studies was only partial, suggesting the participation of other than necroptosis cell death programs which can vary depending on the type of neuronal injury as has already been shown by in vivo (ischemia, traumatic brain injury, spinal cord injury, retina injury) and in vitro studies (e.g., Al-, iron-, 6-OHDA-, or β-amyloidinduced neurotoxicity) (Askalan et al 2015;Chinskey et al 2014;Dai et al 2013;Dong et al 2012;Liu et al 2014;Rosenbaum et al 2010;Qinli et al 2013;Wu et al 2015;Xu et al 2010a;Zhang et al 2008).…”

Section: Introductionmentioning

confidence: 95%

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

et al. 2020

View full text Add to dashboard Cite

Necroptosis, a recently discovered form of non-apoptotic programmed cell death, can be implicated in many pathological conditions including neuronal cell death. Moreover, an inhibition of this process by necrostatin-1 (Nec-1) has been shown to be neuroprotective in in vitro and in vivo models of cerebral ischemia. However, the involvement of this type of cell death in oxidative stress-induced neuronal cell damage is less recognized. Therefore, we tested the effects of Nec-1, an inhibitor of necroptosis, in the model of hydrogen peroxide (H 2 O 2)-induced cell damage in human neuroblastoma SH-SY5Y and murine hippocampal HT-22 cell lines. The data showed that Nec-1 (10-40 μM) attenuated the cell death induced by H 2 O 2 in undifferentiated (UN-) and neuronal differentiated (RA-) SH-SY5Y cells with a higher efficacy in the former cell type. Moreover, Nec-1 partially reduced cell damage induced by 6-hydroxydopamine in UN-and RASH -SY5Y cells. The protective effect of Nec-1 was of similar magnitude as the effect of a caspase-3 inhibitor in both cell phenotypes and this effect were not potentiated after combined treatment. Furthermore, the non-specific apoptosis and necroptosis inhibitor curcumin augmented the beneficial effect of Nec-1 against H 2 O 2-evoked cell damage albeit only in RASH -SY5Y cells. Next, it was found that the mechanisms of neuroprotective effect of Nec-1 against H 2 O 2induced cell damage in SH-SY5Y cells involved the inhibition of lysosomal protease, cathepsin D, but not caspase-3 or calpain activities. In HT-22 cells, Nec-1 was protective in two models of oxidative stress (H 2 O 2 and glutamate) and that effect was blocked by a caspase inhibitor. Our data showed neuroprotective effects of the necroptosis inhibitor, Nec-1, against oxidative stress-induced cell damage and pointed to involvement of cathepsin D inhibition in the mechanism of its action. Moreover, a cell type-specific interplay between necroptosis and apoptosis has been demonstrated.

show abstract

Necroptosis-like Neuronal Cell Death Caused by Cellular Cholesterol Accumulation

Abstract: Edited by Paul FraserAberrant

Cited by 22 publications

References 48 publications

Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells

Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells

Lipid markers and related transcripts during excitotoxic neurodegeneration in kainate‐treated mice

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

Contact Info

Product

Resources

About