Brain oxidatively modified proteins

Figure 18.2 Redox proteomics and oxidatively modified proteins in the brain. Redox proteomics has the potential of detecting disease markers and identifying potential targets for drug therapy in neurodegenerative disorders. Redox proteomics involves the separation of brain proteins followed by detection, usually immunochemically, of oxidatively modified proteins, either from a two-dimensional western blot or from column eluents. Subsequent mass spectrometric analysis of tryptic digests and database searching leads to protein identification.

W. M., Booze, R., Markesbery, W. R., Butterfield, D. A. Proteomic identification of oxidatively modified proteins in Alzheimer s disease brain. Part I creatine kinase BB, glutamine synthase, and ubiq-uitin carboxy-terminal hydrolase L-l. Free Radical Biol. Med. 2002, 33 562-571. 

Butterfield DA, Sultana R. 2007. Redox proteomics identification of oxidatively modified brain proteins in Alzheimer s disease and mild cognitive impairment Insights into the progression of this dementing disorder. J Alzheimers Dis 12 61-72. 

Soluble N-ethylmaleimidesensitive factor (NSF) attachment protein (y-SNAP) is another protein found to be oxidatively modified in AD brain, and this protein is important in vesicular transport for neurotransmitter release, hormone secretion, and mitochondrial integrity. Hence, oxidation may lead to an altered neurotransmission system and impaired learning and memory in AD (Masliah et al, 1994 Scheff and Price, 2003 Sultana et al, 2006d). 

Butterfield DA, Kanski J (2002) Methionine residue 35 is critical for the oxidative stress and neurotoxic properties of Alzheimer s amyloid beta-peptide 1-42. Peptides 23 1299-1309 Butterfield DA, Lauderback CM (2002) Lipid peroxidation and protein oxidation in Alzheimer s disease brain potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med 32 1050-1060 Butterfield DA, Poon HF, St Clair D, Keller JN, Pierce WM, Klein JB, Markesbery WR (2006a) Redox proteomics identification of oxidatively modified hippocampal proteins in mUd cognitive impairment Insights into the development of Alzheimer s disease. Neurobiol Dis 22(2) 223-232... 

Oxidative damage to cells is a common phenomenon, and quality control of modified proteins is important to maintain normal cellular functions. In the cytoplasm, nucleus, and endoplasmic reticulum, the proteasome is involved in the removal of various types of proteins such as ubiquinated, misfolded, or unfolded proteins, and oxidized proteins. Abnormal inhibition of proteasome may contribute to neuro-degenerative diseases such as Alzheimer disease, Parkinson disease, Lewy body dementia, and Huntington disease [31-40]. Neuromuscular diseases, such as sporadic inclusion-body myositis (s-IBM) share several phenotypes described in the brain tissues of Alzheimer and Parkinson disease patients [41]. One such similarity to Alzheimer disease is the accumulation of amyloid-P (AP), phosphory-lated tau (p-tau), and ubiquitin, which are often found within these aggregates [42, 43]. In s-IBM patients, significant proteasome abnormalities were identified including, increased 26 S proteasome expression and abnormal accumulation of 26S proteasome, but reduced proteasome activities [44]. The inverse relationship between increased expression... 

There are several mechanisms whereby antidepressants can modify intracellular events that occur proximal to the posts)maptic receptor sites. Most attention has been paid to the actions of antidepressants on those pathways that are controlled by receptor-coupled second messengers (such as cyclic AMP, inositol triphosphate, nitric oxide and calcium binding). However, it is also possible that chronic antidepressant treatment may affect those pathways that involve receptor interactions with protein tyrosine kinases, by increasing specific growth factor synthesis or by regulating the activity of proinflammatory cytokines. These pathways are particularly important because they control many aspects of neuronal function that ultimately underlie the ability of the brain to adapt and respond to pharmacological and environmental stimuli. One mechanism whereby antidepressants could increase the s)mthesis of trophic factors is... 

Pamplona, R., Dalfo, E., Ayala, V., Bellmunt, M. J., Prat, J., Ferrer, I., and Portero-Otin, M. (2005). Proteins in human brain cortex are modified by oxidation, glycoxidation and lipoxidation Effects of Alzheimer s disease and identification of lipoxidation targets. ]. Biol. Chem. 280, 21522-21530. 

Copper is essential for some of the enzymes that have a role in brain metabolism. Sophisticated mechanisms balance copper import and export to ensure proper nutrient levels (homeostasis) while minimizing toxic effects. Several neurodegenerative diseases including AD are characterized by modified copper homeostasis. This change seems to contribute either directly or indirectly to increased oxidative stress, an important factor in neuronal toxicity. The association of misfolded proteins and modified copper homeostasis appears to be important in the pathological progression of AD [Donnelly et al., 2007],... 

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