Ethanol-Induced Changes in the Content of Triglycerides, Ceramides, and Glucosylceramides in Cultured Neurons

Saito, Mariko; Shimada, Mitsuo; Cooper, Thomas B.; Vadász, Csaba

doi:10.1097/01.alc.0000175011.22307.61

Cited by 45 publications

(40 citation statements)

References 64 publications

(76 reference statements)

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“…We demonstrated here that the activities of RhoA, Rac1, and Cdc42 were all decreased in TDP-43-depleted cells, suggesting that knockdown of TDP-43 induces inhibition of neurite outgrowth and cell death through the inactivation of Rho family GTPases. There was no evidence of apoptosis mediated by TDP-43 knockdown in the model we used perhaps because of the biological characteristics of Neuro-2a cells in which the induction of apoptosis is known to be difficult (34,35). In support of this view, we confirmed that GGTI-298 had no effect on apoptosis in Neuro-2a cells under the present conditions (Fig.…”

Section: Tdp-43 As a Regulator Of Rho Familysupporting

confidence: 81%

TDP-43 Depletion Induces Neuronal Cell Damage through Dysregulation of Rho Family GTPases

Iguchi¹,

Katsuno

Niwa

et al. 2009

Journal of Biological Chemistry

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The 43-kDa TAR DNA-binding protein (TDP-43) is known to be a major component of the ubiquitinated inclusions characteristic of amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Although TDP-43 is a nuclear protein, it disappears from the nucleus of affected neurons and glial cells, implicating TDP-43 loss of function in the pathogenesis of neurodegeneration. Here we show that the knockdown of TDP-43 in differentiated Neuro-2a cells inhibited neurite outgrowth and induced cell death. In knockdown cells, the Rho family members RhoA, Rac1, and Cdc42 GTPases were inactivated, and membrane localization of these molecules was reduced. In addition, TDP-43 depletion significantly suppressed protein geranylgeranylation, a key regulating factor of Rho family activity and intracellular localization. In contrast, overexpression of TDP-43 mitigated the cellular damage caused by pharmacological inhibition of geranylgeranylation. Furthermore administration of geranylgeranyl pyrophosphate partially restored cell viability and neurite outgrowth in TDP-43 knockdown cells. In summary, our data suggest that TDP-43 plays a key role in the maintenance of neuronal cell morphology and survival possibly through protein geranylgeranylation of Rho family GTPases.The 43-kDa TAR DNA-binding protein 2 has recently been identified as a major component of the ubiquitinated inclusions characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinpositive inclusions (1, 2). Subsequently several point mutations located in the glycine-rich domain of TDP-43 have been identified as the disease-causing mutations of familial and sporadic ALS (3-7). TDP-43 has been shown to be a fundamental component of ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions as well as that of neuronal dystrophic neurites in the affected neurons or glial cells in these neurodegenerative diseases. TDP-43 is known to regulate gene transcription, exon splicing, and exon inclusion through interactions with RNA, heterogeneous nuclear ribonucleoproteins, and nuclear bodies (8 -12). Recently it has been reported that TDP-43 stabilizes human low molecular weight neurofilament mRNA through direct interaction with the 3Ј-untranslated region (13) and that it regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression (14). However, the physiological function of TDP-43 in the central nervous system has not been fully elucidated, and it remains unclear how this protein is implicated in the pathogenesis of neurodegeneration.The Rho family of GTPases are members of the Ras superfamily and are known for regulating actin cytoskeletal dynamics (15-18). RhoA, Rac1, and Cdc42, the most studied proteins of this family, also modulate functions such as cell movement, motility, transcription, cell growth, and cell survival (18). In neurons, RhoA, Rac1, and Cdc42 have been shown to regulate neurite outgrowth (19 -21).Although TDP-43 ...

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Section: Tdp-43 As a Regulator Of Rho Familysupporting

confidence: 81%

TDP-43 Depletion Induces Neuronal Cell Damage through Dysregulation of Rho Family GTPases

Iguchi¹,

Katsuno

Niwa

et al. 2009

Journal of Biological Chemistry

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“…The KO mice may need to eliminate a higher number of degenerating neurons than WT mice, or the endosomal/ lysosomal pathway may be disrupted in the KO mice because of the lack of GM2/GD2 or downstream gangliosides. In addition, the accumulation of GM2 or GD3/GM3 may be promoted by enhanced lipogenesis and augmented de novo ceramide/ganglioside synthesis by ethanol, as we have shown previously in C57BL/6By mice ( 15,17 ) and in cultured neurons ( 47 ). While mechanisms of preferential elevation of GM2 in phagocytic microglia in WT mice remain to be elucidated, accumulation of simple gangliosides, such as GM3 and GM2, have often been reported in lysosomal storage diseases, neurodegenerative diseases, and neuroinjury models ( 23, 27-29, 34-36, 50, 51 ).…”

Section: Discussionsupporting

confidence: 61%

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

Saito

Hui

et al. 2015

Journal of Lipid Research

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“…In this study, we found that the formation of NBD-GlcCer was reduced by Hsp90 inhibitors with and without Na 3 VO 4 , and that treatment with Na 3 VO 4 stimulated the formation of NBD-caproic acid, a counterpart of sphingosine, and the formation was markedly decreased by inhibitors of Hsp90 in PC12 cells (Table 1). Saito et al (2005) reported that ethanol-induced toxicity in several neuronal cells accompanied a decrease in the GlcCer level, and proposed that GlcCer per se or the conversion of ceramide to GlcCer has anti-apoptotic effects. Thus, treatment of PC12 cells with Hsp90 inhibitors may cause and/or enhance cytotoxicity by reducing survival signaling mediated by sphingosine-1-phosphate and GlcCer, in addition to the possible accumulation of ceramide.…”

Section: Discussionmentioning

confidence: 99%

Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells

et al. 2012

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Ethanol-Induced Changes in the Content of Triglycerides, Ceramides, and Glucosylceramides in Cultured Neurons

Cited by 45 publications

References 64 publications

TDP-43 Depletion Induces Neuronal Cell Damage through Dysregulation of Rho Family GTPases

TDP-43 Depletion Induces Neuronal Cell Damage through Dysregulation of Rho Family GTPases

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells

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