Autophagy-mediated clearance of ubiquitinated mutant huntingtin by graphene oxide

Jin, Peipei; Wei, Pengfei; Zhang, Yunjiao; Lin, Jun; Sha, Rui; Hu, Yi; Zhang, Jiqian; Zhou, Wei; Yao, Han; Li, Ren; Yang, James Y.; Liang, Yanchun; Wen, Longping

doi:10.1039/c6nr07255k

Cited by 43 publications

(37 citation statements)

References 41 publications

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“…In this study, the expression of PI3K/Akt/mTOR, a main upstream signaling pathway of autophagy, was further studied by Western blot analysis, and the results suggested that GO-induced autophagy was activated by suppressing the PI3K/Akt/mTOR signaling pathway. Previous studies have shown that GO-activated autophagy does not involve the mTOR pathway but depends on activation of the PtdIns3K and MEK/ERK1/2 signaling pathways [61]. A recent study also suggested that downregulation of PI3K/Akt/mTOR signaling pathways leads to GOinduced autophagy [31].…”

Section: Discussionmentioning

confidence: 99%

The interrupted effect of autophagic flux and lysosomal function induced by graphene oxide in p62-dependent apoptosis of F98 cells

Zhang

Feng

et al. 2020

J Nanobiotechnol

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Background: Graphene oxide (GO) nanoparticles (NPs) have been widely applied in various fields, especially in biomedical applications. Extensive studies have suggested that GO can pass through the blood-brain barrier (BBB) and induce abnormal autophagy and cytotoxicity in the central nervous system (CNS). However, the effect and specific mechanism of GO on astrocytes, the most abundant cells in the brain still has not been extensively investigated. Results: In this study, we systematically explored the toxicity and mechanism of GO exposure in the rat astrogliomaderived F98 cell line using molecular biological techniques (immunofluorescence staining, flow cytometry and Western blot) at the subcellular level and the signaling pathway level. Cells exposed to GO exhibited decreased cell viability and increased lactate dehydrogenase (LDH) release in a concentration-and time-dependent manner. GO-induced autophagy was evidenced by transmission electron microscopy (TEM) and immunofluorescence staining. Western blots showed that LC3II/I and p62 were upregulated and PI3K/Akt/mTOR was downregulated. Detection of lysosomal acidity and cathepsin B activity assay indicated the impairment of lysosomal function. Annexin V-FITC-PI detection showed the occurrence of apoptosis after GO exposure. The decrease in mitochondrial membrane potential (MMP) with an accompanying upregulation of cleaved caspase-3 and Bax/Bcl-2 further suggested that endogenous signaling pathways were involved in GO-induced apoptosis. Conclusion: The exposure of F98 cells to GO can elicit concentration-and time-dependent toxicological effects. Additionally, increased autophagic response can be triggered after GO treatment and that the blocking of autophagy flux plays a vital role in GO cytotoxicity, which was determined to be related to dysfunction of lysosomal degradation. Importantly, the abnormal accumulation of autophagic substrate p62 protein can induce capase-3-mediated apoptosis. Inhibition of abnormal accumulation of autophagic cargo could alleviate the occurrence of GO-induced apoptosis in F98 cells.

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Section: Discussionmentioning

confidence: 99%

The interrupted effect of autophagic flux and lysosomal function induced by graphene oxide in p62-dependent apoptosis of F98 cells

Zhang

Feng

et al. 2020

J Nanobiotechnol

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“…These data demonstrate the important role of autophagy in midazolam-induced mHtt protein accumulation. UPS, another important pathway for proteolysis in eukaryotes, could be inhibited by MG132 [22]. However, there was no significant change in the percentage of GFP-Htt (Q74) puncta or in GFP-Htt (Q74) protein levels between midazolam-and MG132 plus midazolamtreated cells (Fig.…”

Section: Role Of Autophagy In Midazolam-induced Gfp-htt (Q74) Accumulmentioning

confidence: 88%

“…In these cells, GFP-Htt (Q74) protein was observed as bright punctate dots [22], indicating the formation of aggregates. As shown in Fig.…”

Section: Midazolam Induced Gfp-htt (Q74) Accumulationmentioning

confidence: 99%

Midazolam Enhances Mutant Huntingtin Protein Accumulation via Impairment of Autophagic Degradation In Vitro

Zhang¹,

Dai²,

Geng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Autophagy is a well-known pathway to “clean” the misfolded mutant huntingtin protein (mHtt), which plays a considerable role in polyglutamine diseases. To date, there have been few studies of the choice of anesthetic during surgery in patients with polyglutamine diseases and evaluation of the effects and underlying mechanisms of anesthetics in these patients. Methods: GFP-Htt (Q74)-PC12 cells, which stably express green fluorescent protein-tagged Htt protein containing 74 glutamine repeating units, were used throughout this study. Cells were treated with 15 μM midazolam and 100 mM trehalose (positive control), and the induction of autophagy and autophagic degradation were assessed by detecting changes in autophagy-related proteins and substrates, and cell viability was assessed using the MTT assay. Overexpression of cathepsin D by plasmid transfection was used to restore midazolam-impaired autophagic degradation. Results: Midazolam increased intracellular mHtt levels in a time- and dose-dependent manner. Additionally, enhancing or blocking autophagic flux by trehalose or chloroquine could decrease or increase midazolam-induced mHtt elevation, respectively. Midazolam induced autophagy in the mTOR-dependent signaling pathway, but autophagic degradation was impaired, with a continuous rise in p62 and LC3 II levels and decrease in cathepsin D. However, overexpression of cathepsin D reversed the effects of midazolam. Midazolam led to a 20% decrease in GFP-Htt (Q74)-PC12 cell viability, which could be abrogated by overexpression of cathepsin D. Conclusions: Midazolam increased mHtt levels and decreased Htt (Q74)-PC12 cell viability via impairment of autophagic degradation, which could be restored by overexpression of cathepsin D.

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“…In Eu III (OH) 3 nanorod‐induced autophagy, the autophagy induction is regulated not only by MEK/ERK1/2 signaling pathway but also by AKT–mTOR and AMPK‐independent pathway, and the activation of autophagy caused by Eu III (OH) 3 nanorods is dose‐ and time dependent . In another research, GO‐induced autophagy was shown to be mediated by PI3K and was dependent on MEK/ERK1/2 but not on mTOR signaling pathway in PC12 and Hela cells . To further enhance or reduce the autophagy degree and more exactly depict the regulatory mechanisms of NM‐phagy, some interference including autophagy drug regulator (such as 3‐MA and trehalose) or gene silencing are usually used in NM‐phagy…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

“…For example, compared to larger one, the small silica nanoparticles (SNPs) enhance the endocytosis properties, which probably due to the fact that small‐sized NMs can be rapidly and favorably internalized into cells than large ones . The fact may also reason the observation that small graphene oxide (GO)‐induced autophagy‐mediated clearance of huntingtin is more effective than large one, while, in some cases, the larger NMs show higher efficient endocytosis than small one, such as the AuNPs . The effect of shape on endocytosis has been described by many researches.…”

Section: Endocytosis Pathways Of Nmsmentioning

confidence: 99%

Crosstalk between Autophagy and Nanomaterials: Internalization, Activation, Termination

Wei

Duan

2018

Adv. Biosys.

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NMs, SiO 2 -based NMs, lipid-based NMs, polymer-based NMs, polyethylene glycol (PEG)-based NMs, and other types NMs. Alternatively, according to the physical and chemical properties of NMs, they can be classified into soft NMs, referring to lipidor polymer-based NMs, and hard NMs such as mental-or carbon-based NMs.With the development of nanotechnology, these materials have been widely applied in various fields. [3] For example, ZnO nanoparticles (NPs) can serve as antimicrobial agents; [4] TiO 2 NPs are used in sunscreen lotions; [5] lipid/polymeric-based NPs are applied in drug/gene delivery; [6] QDs are used as florescent probes; [7] and magnetic NPs are applied in magnetic resonance imaging. [8] The NMs not only effectively enhance cellular and subcellular targeting of drugs and the effect of imaging, but also rise the attention on the importance of affirming the effect of NMs on biological systems. It has been recognized that NMs are capable of modulating autophagy. The modulation of NMs on autophagy may be beneficial, since the combinative effect of the NMs' features and autophagy functions is capable of enhancing the accuracy of diagnosis and efficiency of therapies. For example, AgNPs could be a fascinating tool in infections and antimicrobial immunity in that the NM-phagy can modulate the antiviral/antibacterial defenses. [9] In this process, AgNPs lead to the disorganization of mitochondrial network and contribute to the modulation of autophagy (both Rab9-dependent alternative autophagy and Atg-5-dependent classical autophagy) by blocking the autophagic flux. Additionally, AgNPs can reduce the production of CCL-5 and interferon (IFN)-β in influenza-infected cells through the Rab9-dependent alternative autophagy.Autophagy, a "self-digestion" biological process of cellular degradation, is induced when cells are subjected to unfavorable factors, including starvation or drug treatments, accumulation of the damaged organelles, and misfolded proteins. The autophagic process refers to the cargo encompassed into autophagosome and delivery of cargo to lysosomes to degrade and to release macromolecules back into the cytosol. [10] If the "self-digestion" gets out of control, the autophagy dysfunction, including excessive autophagy induction or suppression of autophagy flux, will induce serious diseases, such as cancer, neurodegenerative diseases, immunological diseases, innate turbulence, and even cell death. [11] Therefore, autophagy is Nanomaterials (NMs) are comprehensively applied in biomedicine due to their unique physical and chemical properties. Autophagy, as an evolutionarily conserved cellular quality control process, is closely associated with the effect of NMs on cells. In this review, the recent advances in NM-induced/ inhibited autophagy (NM-phagy) are summarized, with an aim to present a comprehensive description of the mechanisms of NM-phagy from the perspective of internalization, activation, and termination, thereby bridging autophagy and nanomaterials. Several possible mechanisms are extensively ...

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Autophagy-mediated clearance of ubiquitinated mutant huntingtin by graphene oxide

Cited by 43 publications

References 41 publications

The interrupted effect of autophagic flux and lysosomal function induced by graphene oxide in p62-dependent apoptosis of F98 cells

The interrupted effect of autophagic flux and lysosomal function induced by graphene oxide in p62-dependent apoptosis of F98 cells

Midazolam Enhances Mutant Huntingtin Protein Accumulation via Impairment of Autophagic Degradation In Vitro

Crosstalk between Autophagy and Nanomaterials: Internalization, Activation, Termination

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