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

Kokubo, June; Nagatani, Naoki; Hiroki, Katsunori; Kuroiwa, Kenji; Watanabe, Nobuo; Arai, Takao

doi:10.1247/csf.07038

Cited by 19 publications

(21 citation statements)

References 31 publications

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“…The former study showed no significant impairment of neurite outgrowth at 4-HNE concentrations below 25 lM, and found no significant cell death. These discrepancies could be the result of differences in cell types, period of 4-HNE exposure and extent of cell density (Kokubo et al 2008). For example, within the present study there was enhanced sensitivity of the mouse DRG neuronal cultures to 4-HNE.…”

Section: Discussioncontrasting

confidence: 52%

“…Earlier studies have also demonstrated the ability of 4-HNE to act as a signaling molecule, which induces a variety of cellular processes (Awasthi et al 2003;Forman et al 2003). In addition, 4-HNE has been shown to inhibit neurite outgrowth, disrupt microtubules, and modify tubulin in Neuro 2A neuroblastoma cells (Neely et al 1999;Kokubo et al 2008), and it's cytotoxic and genotoxic effects have been demonstrated in cerebral endothelial cells (Karlhuber et al 1997).…”

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confidence: 96%

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4-Hydroxy-2-Nonenal Induces Mitochondrial Dysfunction and Aberrant Axonal Outgrowth in Adult Sensory Neurons that Mimics Features of Diabetic Neuropathy

et al. 2009

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Modification of proteins by 4-hydroxy-2-nonenal (4-HNE) has been proposed to cause neurotoxicity in a number of neurodegenerative diseases, including distal axonopathy in diabetic sensory neuropathy. We tested the hypothesis that exposure of cultured adult rat sensory neurons to 4-HNE would result in the formation of amino acid adducts on mitochondrial proteins and that this process would be associated with impaired mitochondrial function and axonal regeneration. In addition, we compared 4-HNE-induced axon pathology with that exhibited by neurons isolated from diabetic rats. Cultured adult rat dorsal root ganglion (DRG) sensory neurons were incubated with varying concentrations of 4-HNE. Cell survival, axonal morphology, and level of axon outgrowth were assessed. In addition, video microscopy of live cells, western blot, and immunofluorescent staining were utilized to detect protein adduct formation by 4-HNE and to localize actively respiring mitochondria. 4-HNE induced formation of protein adducts on cytoskeletal and mitochondrial proteins, and impaired axon regeneration by approximately 50% at 3 microM while having no effect on neuronal survival. 4-HNE initiated formation of aberrant axonal structures and caused the accumulation of mitochondria in these dystrophic structures. Neurons treated with 4-HNE exhibited a distal loss of active mitochondria. Finally, the distal axonopathy and the associated aberrant axonal structures generated by 4-HNE treatment mimicked axon pathology observed in DRG sensory neurons isolated from diabetic rats and replicated aspects of neurodegeneration observed in human diabetic sensory neuropathy.

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Section: Discussioncontrasting

confidence: 52%

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confidence: 96%

4-Hydroxy-2-Nonenal Induces Mitochondrial Dysfunction and Aberrant Axonal Outgrowth in Adult Sensory Neurons that Mimics Features of Diabetic Neuropathy

et al. 2009

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“…Consequently, increased lipid peroxidation might be responsible for the neuronal degeneration and death characteristic of AD. In support is the fact that HNE, a lipid peroxidation product is cytotoxic to cultured neuronal cells via impairment of Na + , K + -ATPase (15), disruptions of microtubule structure (7,20), caspase-3 activation, and cytochrome c release (6). The distribution of the HNE adduct differed among CA sectors in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Elevated levels of 4-hydroxynonenal-histidine Michael adduct in the hippocampi of patients with Alzheimer's disease

Fukuda

Kanou²,

Shimada

et al. 2009

Biomed. Res.

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Alzheimer's disease (AD) is among the most common causes of progressive cognitive impairment in humans and is characterized by neurodegeneration in the brain. Lipid peroxidation is thought to play a role in the pathogenesis of AD. 4-hydroxynonenal (HNE) results from peroxidation of polyunsaturated fatty acids and it in turn gives evidence of lipid peroxidation in vivo. HNE reacts with protein histidine residue to form a stable HNE-histidine Michael adduct. To clarify the influence of lipid peroxidation on the pathogenesis of AD, we measured HNE-histidine Michael adduct in hippocampi from four AD patients and four age-matched controls by means of semiquantitative immunohistochemistry using a specific antibody to cyclic hemiacetal type of HNE-histidine Michael adduct. This antibody does not react with the ring-opened form of HNE-histidine Michael adduct and the pyrrole form of HNE-lysine Michael adduct. The HNE adduct was detected in the hippocampi of both AD and control donors, especially in the CA2, CA3 and CA4 sectors. Immunoreactive intensity of HNE adduct in these sectors were significantly higher in AD patients than in the controls. The HNE adduct was found in the perikarya of pyramidal cells in the hippocampus. These results show that the hippocampi of patients with AD undergo lipid peroxidation and imply that this activity underlies the production of cytotoxic products such as HNE that are responsible for the pathogenesis of AD.The progressive cognitive impairment of Alzheimer's disease (AD) is associated with neuronal loss as well as the formation of neurofibrillary tangles (NFTs) and senile plaques in the brain (25). Free radical-mediated oxidative damage, energy depletion, deposition of amyloids and NFTs, excitotoxicity, and vascular endothelial cell damage are all thought to participate in the pathogenesis of AD (13). Oxygen-derived free radicals, byproducts of respiration, cause oxidative damage to cellular biomolecules including lipids, proteins and nucleic acids. The brain seems to be especially vulnerable to lipid peroxidation by free radicals, because it consumes approximately one-fifth of humans' oxygen intake, has a relative paucity of antioxidant systems and contains high concentrations of polyunsaturated fatty acids (PUFAs) (11). Lipid peroxidation results in structural damage to membranes and generation of secondary products such as reactive aldehydes

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“…Various diseases involve proteins modified by HNE and protein cross-linking through HNE adducts contributes to disease pathogenecities [14,[16][17][18]. Here, we showed that spectrins are the primary targets of HNE, and that HNE-modified spectrins generate irreversibly cross-linked aggregates in human RBCs.…”

Section: Discussionmentioning

confidence: 74%

“…HNE is a highly reactive electrophile that reacts with the side chains of various amino acid residues, including Cys, His, and Lys, to form Michael adducts [10,13]. Protein modification by HNE causes serious detrimental effects in the cell, due to the resulting functional defects and cross-linking of proteins [14][15][16][17][18]. HNE also accumulates in RBCs [19], leading to the covalent modification of membrane proteins [20].…”

Section: Introductionmentioning

confidence: 99%

The covalent modification of spectrin in red cell membranes by the lipid peroxidation product 4-hydroxy-2-nonenal

Arashiki

Otsuka

Ito

et al. 2010

Biochemical and Biophysical Research Communications

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Spectrin strengthens the red cell membrane through its direct association with membrane lipids and through protein-protein interactions. Spectrin loss reduces the membrane stability and results in various types of hereditary spherocytosis. However, less is known about acquired spectrin damage. Here, we showed that α-and β-spectrin in human red cells are the primary targets of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) by immunoblotting and mass spectrometry analyses. The level of HNE adducts in spectrin (particularly α-spectrin) and several other membrane proteins was increased following the HNE treatment of red cell membrane ghosts prepared in the absence of MgATP. In contrast, ghost preparation in the presence of MgATP reduced HNE adduct formation, with preferential β-spectrin modification and increased cross-linking of the HNE-modified spectrins. Exposure of intact red cells to HNE resulted in selective HNE-spectrin adduct formation with a similar preponderance of HNE-β-spectrin modifications. These findings indicate that HNE adduction occurs preferentially in spectrin at the interface between the skeletal proteins and lipid bilayer in red cells and suggest that HNE-spectrin adduct aggregation results in the extrusion of damaged spectrin and membrane lipids under physiological and disease conditions.

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

Cited by 19 publications

References 31 publications

4-Hydroxy-2-Nonenal Induces Mitochondrial Dysfunction and Aberrant Axonal Outgrowth in Adult Sensory Neurons that Mimics Features of Diabetic Neuropathy

4-Hydroxy-2-Nonenal Induces Mitochondrial Dysfunction and Aberrant Axonal Outgrowth in Adult Sensory Neurons that Mimics Features of Diabetic Neuropathy

Elevated levels of 4-hydroxynonenal-histidine Michael adduct in the hippocampi of patients with Alzheimer's disease

The covalent modification of spectrin in red cell membranes by the lipid peroxidation product 4-hydroxy-2-nonenal

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