Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins

doi:10.1016/S0047-6374(01)00249-4

Mechanisms of Ageing and Development

Volume 122, Issue 9, 15 July 2001, Pages 945-962

https://doi.org/10.1016/S0047-6374(01)00249-4 Get rights and content

Abstract

Protein oxidation, one of a number of brain biomarkers of oxidative stress, is increased in several age-related neurodegenerative disorders or animal models thereof, including Alzheimer's disease, Huntington's disease, prion disorders, such as Creutzfeld–Jakob disease, and α-synuclein disorders, such as Parkinson's disease and frontotemporal dementia. Each of these neurodegenerative disorders is associated with aggregated proteins in brain. However, the relationship among protein oxidation, protein aggregation, and neurodegeneration remain unclear. The current rapid progress in elucidation of mechanisms of protein oxidation in neuronal loss should provide further insight into the importance of free radical oxidative stress in these neurodegenerative disorders.

Introduction

Oxidative stress, an imbalance toward the prooxidant side of the prooxidant/antioxidant homeostasis, occurs in several brain neurodegenerative disorders and animal models thereof (Markesbery, 1997, Butterfield et al., 2001, Varadarajan et al., 2000a). Among these neurodegenerative brain disorders are those in which protein aggregation is observed, including Alzheimer's disease (AD), Huntington's disease (HD), prion disorders such as Creutzfeld–Jakob disease (CJD), and disorders with aggregated α-synuclein, such as Parkinson's disease (PD) and frontotemporal dementia (FTD), also called diffuse Lewy body disease (LBD). In addition to aggregated α-synuclein in the latter disorders, AD, HD, and prion disorders are characterized by the presence of aggregated proteins: amyloid β-peptide (Aβ), huntingtin and prions, respectively. What the relationships might be among protein aggregation, oxidative stress, and neurodegeneration remain uncertain. It is of note that each of these disorders has a characteristic pathology and symptomology, but each, nevertheless, has the property of protein aggregation. While newer research has questioned the relationship between protein fibril formation and disease, it is quite likely that some sort of protein aggregation is of pathological consequence in each of these brain neurodegenerative disorders. In addition to protein oxidation, the major subject of this review, other leading biomarkers of oxidative stress include, among others, lipid peroxidation, reactive oxygen species (ROS) and reactive nitrogen species (RNS) formation, mitochondrial dysfunction, antioxidant enzyme upregulation, advanced glycation endproducts and DNA and RNA oxidation (Butterfield and Stadtman, 1997).

In this review, mechanisms and indices of protein oxidation will be reviewed, followed by a review of brain protein oxidation in each of the above-mentioned disorders that are associated with protein aggregation.

Section snippets

Mechanisms of protein oxidation

Oxidation of proteins normally is caused by free radicals, and this process, from a chemical thermodynamics standpoint, is an exothermic event. Oxidative reactions of peptides are mediated mainly, but not only, by the hydroxyl radical (OH) that can be produced by decomposition of hydrogen peroxide in presence of redox metals (Cu⁺ and Fe²⁺) (Butterfield and Stadtman, 1997). There are two possible oxidative pathways that can occur: (a) backbone oxidation and (b) side-chain oxidation (Scheme 1).

Determination of extent of protein oxidation

Protein carbonyls, introduced to proteins via direct oxidation of the protein backbone, amino acid side-chains, or by reaction with alkenals, as noted above, are an index of protein oxidation and can be assayed by formation of the 2,4-dinitrophenylhydrazone (DNPH) covalent adduct (Butterfield and Stadtman, 1997). Prior studies relied almost exclusively on spectrophotometric quantification of protein carbonyls, but recent studies have employed immunochemical detection of the DNPH-protein adduct (

Oxidative modification of neuronal proteins in Alzheimer's disease: role of Aβ

There is considerable evidence consistent with the importance of oxidative stress in the pathology of AD (for recent reviews, see Markesbery, 1997, Markesbery and Carney, 1999, Christen, 2000, Smith et al., 2000, Varadarajan et al., 2000a). Evidence supporting the notion of free radical oxidative stress in AD brain includes: increased redox-active metal ions in AD brain; increased lipid peroxidation detected by decreased levels of polyunsaturated fatty acids and increased levels of the lipid

Protein oxidation in Huntington's disease

Huntington's disease (HD) is characterized by behavioral abnormalities, cognitive impairment and involuntary choreiform movements (Chase et al., 1979). The disease is caused by a mutation in gene IT15 on chromosome 4, resulting in expression of a glutamine-rich protein ‘huntingtin’ (Bonilla, 2000). Huntingtin aggregates into long fibrillar strands that are localized primarily to the nucleus, but may be located elsewhere in striatal neuron (Bonilla, 2000). The normal function of huntingtin and

Evidence of protein oxidation in prion disorders

Prion diseases are neurodegenerative disorders characterized by progressive neuronal death, early synaptic loss, formation of neuroamyloid protein aggregation, and the development of dementia (Prusiner, 1998). Prions that are responsible for the onset of the disease primarily consist of a prion protein. This protein exists in two distinct conformations. The normal, protease-sensitive, primarily α-helical structure (PrP^C) undergoes a conformational change leading to formation of a β-sheet-rich,

Protein oxidation in neurodegenerative disorders associated with α-synuclein

Several neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease, and dementia with Lewy bodies (DLB), are characterized by α-synuclein-containing plaques in brain (Iwai, 2000).

The role of Aβ-derived oxidative stress in toxicity and pathology of AD was discussed above. However, SP also contain other components, including the so-called non-Aβ component of Alzheimer's disease (NAC). NAC has at least 35 amino acids corresponding to residues 61–95 of a 140 amino acid

Conclusion

Alzheimer's disease, Huntington's disease, prion disorders such as Creutzfeld–Jakob disease, and α-synuclein-related disorders such as Parkinson's disease and frontotemporal dementia, though different disorders caused by different genetic or environmental insults and affecting different brain regions, may have a common underlying molecular basis, namely, oxidative stress. As the brain ages, intrinsic oxidative stress increases as a consequence of diminished antioxidant defense capabilities (

Acknowledgements

This work was supported in part by grants from NIH to D.A.B. [AG-05119; AG-10836; AG-12423].

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ReviewBrain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins

Abstract

Introduction

Section snippets

Mechanisms of protein oxidation

Determination of extent of protein oxidation

Oxidative modification of neuronal proteins in Alzheimer's disease: role of Aβ

Protein oxidation in Huntington's disease

Evidence of protein oxidation in prion disorders

Protein oxidation in neurodegenerative disorders associated with α-synuclein

Conclusion

Acknowledgements

Free Rad. Biol. Med.

Prog. Neurobiol.

Exp. Neurol.

Meth. Enzymol.

Adv. Cell Aging Gerontol.

Am. J. Clin. Nutr.

Lancet

J. Struct. Biol.

Free Rad. Biol. Med.

Neuron

Neuroscience

Free Rad. Biol. Med.

J. Nutr.

Biochim. Biophys. Acta

FEBS Lett.

Free Rad. Biol. Med.

Neuroscience

Cell

Brain Res.

Brain Res.

J. Neurol. Sci.

Free Rad. Biol. Med.

Exp. Neurol.

Brain Res.

Neurosci. Lett.

Cell

Free Rad. Biol. Med.

Neuron

Cell

Biochim. Biophys. Acta

J. Biol. Chem.

Prog. Brain Res.

Glutamine synthetase-induced neurotoxicity accompanied by abrogation of fibril formation and amyloid β-peptide fragmentation

J. Neurochem.

Oxidative modification of creatine kinase BB in Alzheimer's disease brain

J. Neurochem.

Oxidative modification of glutamine synthetase by amyloid beta peptide

Free Rad. Res.

Oxidation of cytosolic proteins and expression of creatine kinase BB in frontal cortex in different neurodegenerative disorders

Dement. Geriatr. Cogn. Disord.

No evidence for increased oxidative damage to lipids, proteins, or DNA in Huntington's disease

J. Neurochem.

Oxidative damage and tyrosine nitration from peroxynitrite

Chem. Res. Toxicol.

4-hydroxynonenal, a lipid peroxidation product, impairs glutamate transport in cortical astrocytes

Glia

Toxicity of non-abeta component of Alzheimer's disease amyloid, and N-terminal fragments thereof, correlates to formation of beta-sheet structure and fibrils

Eur. J. Biochem.

Huntington disease. A review

Invest. Clin.

Prion protein expression and superoxide dismutase activity

Biochem. J.

The cellular prion protein binds copper in vivo

Nature

Antioxidant activity related to copper binding of native prion protein

J. Neurochem.

Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia

Ann. Neurol.

Oxidative stress in Huntington's disease

Brain Path.

Free radical oxidation of brain proteins in accelerated senescence and its modulation by N-tert-butyl-α-phenylnitrone

Proc. Natl. Acad. Sci. USA

Oxidatively-induced structural alteration of glutamine synthetase assessed by analysis of spin labeled incorporation kinetics: relevance to Alzheimer's disease

J. Neurochem.

Review
Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins