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

The free radical theory of ageing 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. This review focuses on the impact of oxidative and nitrative stress in the ageing 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.