Early α-synuclein lipoxidation in neocortex in Lewy body diseases

Previous studies in Lewy body diseases (LBDs), including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), have shown oxidative stress damage more extended than the expected for the distribution of Lewy pathology. Since malondialdehyde (MDA) can form adducts with lysine residues of proteins, MDA-Lys immunoprecipitation and α-synuclein immunoblotting has been carried out in frontal cortex and substantia nigra homogenates from five patients with PD, five DLB, three iPD and seven aged-matched controls to decipher the extent of lipoxidized α-synuclein in LBDs. MDA-Lys-lipoxidation of α-synuclein in the substantia nigra and frontal cortex has been found in all DLB and PD cases examined, but also in the frontal cortex in 3/3 and in the substantia nigra in 2/3 cases with iPD. In addition, one control case had MDA-Lys-modified α-synuclein in the frontal cortex, and another in the substantia nigra. This work provides evidence of extended lipoxidative modification of α-synuclein in LBDs. Moreover, it demonstrates that α-synuclein lipoxidation is an early event in LBDs which precedes α-synuclein solubility modification and aggregation, and formation of Lewy bodies and neurites.