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

Abstract

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.

Succination is Increased on Select Proteins in the Brainstem of the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) Knockout Mouse, a Model of Leigh Syndrome

“…Increased protein modification by the reactive lipid peroxidation product 4-hydroxy-2-nonenal (HNE) has been described in neurodegenerative diseases (35)(36)(37). Several mitochondrial enzymes, including the pyruvate dehydrogenase, ␣-ketoglutarate dehydrogenase and branched-chain ␣-keto acid dehydrogenase complexes are targets of HNE conjugation (38).…”

Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells

“…[5][6][7][8][9] An important example is 4-hydroxynonenal, a highly reactive lipid peroxidation product that is increased in the brains of stroke victims and neurodegenerative disease, and is capable of forming protein adducts and stimulating the formation of other reactive species. [5][6][7][8][9][10][11][12][13] Physiologically, the concentration of free HNE in human blood ranges from 0.069 ± 0.015 μM for healthy subjects under the age of 30, and increases to 0.107 ± 0.027 μM for individuals over age 70. 14 Pathologically, levels increase substantially due to the initiation of lipid peroxidation with free levels reported in the range of 1-10 μM how cellular metabolic activities regulate autophagy and determine the susceptibility to oxidative stress and ultimately cell death in neuronal cells is not well understood.…”

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant

“…4 Also brain lipids are oxidized in these and other brain diseases, 5,6 suggesting that lipid oxidation may play an important role in the pathogenesis of neurodegenerative diseases. [7][8][9] Oxidized phospholipids generate compounds, such as 4-oxo-2-nonenal and acrolein, which are predominantly toxic to brain cells. 10 Recent evidence suggests that, in addition to autoimmune pathways, the neurological damage in demyelinating diseases such as multiple sclerosis (MS) 11 may also be of neurodegenerative nature.…”