Protein oxidative modifications in the ageing brain: Consequence for the onset of neurodegenerative disease

Abstract

The free radical theory of aging proposes the accumulation of altered, less active and toxic molecules of DNA, RNA, proteins and lipids caused by reactive oxygen species and reactive nitrogen species. Neurodegenerative disorders are characterized by an abnormal accumulation of oxidatively damaged macromolecules inside cells and in the extracellular space. Proteins involved in the formation of aggregates are β-amyloid, tau, α-synuclein, parkin, prion proteins and proteins containing polyglutamine. These abnormal aggregated proteins influence normal cellular metabolism. Additionally, deposition of abnormal proteins induces oxidative stress and proteasomal as well as mitochondrial dysfunction that ultimately lead to neuronal cell death. In this review we focus on the impact of oxidative and nitrative stress in the aging brain and, consequently, on the generation of modified proteins, as these post-translational modifications are assumed to play an important role in the development of neurodegenerative diseases.

Oxidation-induced Structural Changes of Ceruloplasmin Foster NGR Motif Deamidation That Promotes Integrin Binding and Signaling

“…The faster kinetic of Cp deamidation observed in CSF from AD patients compared with the CSF from healthy subjects supports the hypothesis of a generally accelerated protein aging in neurodegenerative diseases, as a consequence of pathological environment (18,19). Based on the observation that after 12 days of aging in the pathological CSF ϳ40% of the Cp were able to bind integrin and given that the Cp concentration in the CSF is ϳ2 g/ml and that its physiological half-life is ϳ5.5 days in vivo (15), it is conceivable that NGR deamidation might occur in patients to an extent that yields functionally relevant concentration of deamidated Cp (ϳ200 ng/ml).…”

“…Similar modifications have been reported for serum Cp during human aging (26). Thus, the Cp alterations observed in Parkinson disease and AD patients might reflect accelerated protein aging, as a consequence of changes in the environmental redox status of pathological CSF (18,19). Therefore, it is plausible that the reported Cp oxidation-induced changes (17) also include Asn deamidation of NGR motifs.…”

“…We previously reported that Cp undergoes oxidative modifications in the CSF of Parkinson disease and AD patients (17), as a consequence of changes in the environmental redox status of pathological CSF (18,19). Cp oxidation causes a decrease in its ferroxidase activity that may have pathological implications (17).…”

The Nervous System Cytoskeleton under Oxidative Stress

“…Oxidative stress causes the aggregation of a number of proteins implicated in neurodegenerative disorders [1]. Mutations that affect the dynein motor machinery are sufficient to cause motor neuron disease.…”

“…Oxidative stress leads to the formation of peroxides and free radicals, which damage proteins, lipids and DNA. Oxidative stress is implicated in various neurodegenerative disorders, largely due to the abnormal accumulation of oxidatively damaged macromolecules, including β-amyloid and Tau [1].…”