Mechanisms of 4-hydroxynonenal-induced neuronal microtubule dysfunction

Neely, M. Diana; Boutté, Angela M.; Milatović, Dejan; Montine, Thomas J.

doi:10.1016/j.brainres.2004.12.027

Cited by 58 publications

(40 citation statements)

References 67 publications

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“…The results also revealed that proteasome β5 serves an important role in the development of TBI. It has been reported that PA28α overexpression is sufficient to upregulate 11S proteasomes (24), enhance proteasome-mediated removal of misfolded and oxidized proteins, as well as protect against oxidative stress in cardiomyocytes; thus, it can results in an increase in proteasomal degradation of abnormal cellular proteins (25). The results of the present study, thus, indicate the potential value of AG and proteasome β5 in healing axonal injury in TBI.…”

Section: Discussionsupporting

confidence: 54%

Inhibition of cytoskeletal protein carbonylation may protect against oxidative damage in traumatic brain injury

Zhang

Huang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Oxidative stress is the principal factor in traumatic brain injury (TBI) that initiates protracted neuronal dysfunction and remodeling. Cytoskeletal proteins are known to be carbonylated under oxidative stress; however, the complex molecular and cellular mechanisms of cytoskeletal protein carbonylation remain poorly understood. In the present study, the expression levels of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) were investigated in PC12 cells treated with H 2 O 2 . Western blot analysis was used to monitor the carbonylation levels of β-actin and β-tubulin. The results indicated that oxidative stress was increased in PC12 cells that were treated with H 2 O 2 for 24 or 48 h. In addition, increased carbonylation levels of β-actin and β-tubulin were detected in H 2 O 2 -treated cells. However, these carbonylation levels were reduced by pretreatment with aminoguanidine, a type of reactive carbonyl species chelating agent, and a similar trend was observed following overexpression of proteasome β5 via transgenic technology. In conclusion, the present study results suggested that the development of TBI may cause carbonylation of cytoskeletal proteins, which would then undermine the stability of cytoskeletal proteins. Thus, the development of TBI may be improved via the inhibition of cytoskeletal protein carbonylation.

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Section: Discussionsupporting

confidence: 54%

Inhibition of cytoskeletal protein carbonylation may protect against oxidative damage in traumatic brain injury

Zhang

Huang

et al. 2016

Experimental and Therapeutic Medicine

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“…A number of target molecules and mechanisms have been suggested to account for the cytotoxicity of HNE (Gadoni et al, 1993;Hu et al, 2002;Mark et al, 1997;Neely et al, 2005;Picklo et al, 1999;Siems et al, 1996). The present study revealed that tubulin, preferentially α-tubulin, undergoes HNE modification in 3Y1 cells, PC12 cells, and primary neurons, although the relative sensitivity to modification of α-tubulin to β-tubulin by HNE differed slightly among cell types ( Fig.…”

Section: Discussionmentioning

confidence: 57%

“…In vitro studies with purified microtubule fractions have shown that the modifications of tubulin by HNE impair the polymerizability (Neely et al, 2005;Olivero et al, 1990). Nevertheless, the precise mechanisms underlying the microtubule disappearance in cell caused by HNE exposure remain to be fully clarified.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Destruction of Microtubule Structures by 4-Hydroxy-2-Nonenal

Kokubo

Nagatani

Hiroki

et al. 2008

Cell Struct. Funct.

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ABSTRACT. A major end product of lipid peroxidation, 4-hydroxy-2-nonenal (HNE), is an electrophilic alkenal and produces Michael adducts with cellular proteins. It is known that exposure of cultured cells to HNE causes rapid disappearance of microtubule networks. In this study we addressed the mechanism. Immunochemical studies revealed that HNE preferentially modified α-tubulin in rat primary neuronal cells, PC12 cells, and rat fibroblast cell line 3Y1 cells. This was morphologically associated with the disappearance of microtubule structures in those cells. In a purified rat brain microtubule fraction, HNE modified unpolymerized tubulin and impaired its polymerizability, with a concomitant increase in insolubilized tubulin. Nevertheless, HNE had a marginal effect on the stability of pre-polymerized microtubules. These results suggest that disruption of microtubule assembly as a result of HNE modification of unpolymerized tubulin, rather than destruction of assembled microtubules, is responsible for the disappearance of microtubule structures in cells exposed to HNE.

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“…Upon HNE modification, a-tubulin is structurally altered, and microtubules depolymerize (79). Therefore, cargo cannot reach its destination and the cytoskeleton is altered (136,137). This could contribute to the notion that synaptic domains are the first to be damaged in AD neurons (109).…”

Section: Energy Dysfunction: Atp Synthase and A-enolasementioning

confidence: 99%

4-Hydroxy-2-Nonenal, a Reactive Product of Lipid Peroxidation, and Neurodegenerative Diseases: A Toxic Combination Illuminated by Redox Proteomics Studies

Perluigi

Coccia

Butterfield

2012

Antioxidants & Redox Signaling

190

133

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Significance: Among different forms of oxidative stress, lipid peroxidation comprises the interaction of free radicals with polyunsaturated fatty acids, which in turn leads to the formation of highly reactive electrophilic aldehydes. Among these, the most abundant aldehydes are 4-hydroxy-2-nonenal (HNE) and malondialdehyde, while acrolein is the most reactive. HNE is considered a robust marker of oxidative stress and a toxic compound for several cell types. Proteins are particularly susceptible to modification caused by HNE, and adduct formation plays a critical role in multiple cellular processes. Recent Advances: With the outstanding progress of proteomics, the identification of putative biomarkers for neurodegenerative disorders has been the main focus of several studies and will continue to be a difficult task. Critical Issues: The present review focuses on the role of lipid peroxidation, particularly of HNE-induced protein modification, in neurodegenerative diseases. By comparing results obtained in different neurodegenerative diseases, it may be possible to identify both similarities and specific differences in addition to better characterize selective neurodegenerative phenomena associated with protein dysfunction. Results obtained in our laboratory and others support the common deregulation of energy metabolism and mitochondrial function in neurodegeneration. Future Directions: Research towards a better understanding of the molecular mechanisms involved in neurodegeneration together with identification of specific targets of oxidative damage is urgently required. Redox proteomics will contribute to broaden the knowledge in regard to potential biomarkers for disease diagnosis and may also provide insight into damaged metabolic networks and potential targets for modulation of disease progression. Antioxid. Redox Signal. 17, 1590-1609.

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Mechanisms of 4-hydroxynonenal-induced neuronal microtubule dysfunction

Cited by 58 publications

References 67 publications

Inhibition of cytoskeletal protein carbonylation may protect against oxidative damage in traumatic brain injury

Inhibition of cytoskeletal protein carbonylation may protect against oxidative damage in traumatic brain injury

Mechanism of Destruction of Microtubule Structures by 4-Hydroxy-2-Nonenal

4-Hydroxy-2-Nonenal, a Reactive Product of Lipid Peroxidation, and Neurodegenerative Diseases: A Toxic Combination Illuminated by Redox Proteomics Studies

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