In parkinsonian substantia nigra, α-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity

alpha-Synuclein (alpha SYN) plays a central role in the neural degeneration of Parkinson's disease (PD) through its conformational change. In PD, alpha SYN, released from the membrane, accumulates in the cytoplasm and forms Lewy body. However, the mechanism behind the translocation and conformational change of alpha SYN leading to the cell death has not been well elucidated. This paper reports that in the dopamine neurons of the substantia nigra containing neuromelanin from PD patients, alpha SYN was modified with acrolein (ACR), an aldehyde product of lipid peroxidation. Histopathological observation confirmed the co-localization of protein immunoreactive to anti-alpha SYN and ACR antibody. By Western blot analyses of samples precipitated with either anti-alpha SYN or anti-ACR antibody, increase in ACR-modified alpha SYN was confirmed in PD brain. Modification of recombinant alpha SYN by ACR enhanced its oligomerization, and at higher ACR concentrations alpha SYN was fragmented and polymerized forming a smear pattern in SDS-PAGE. ACR reduced 20S proteasome activity through the direct modification of the proteasome proteins and the production of polymerized ACR-modified proteins, which inhibited proteasome activity in vitro. These results suggest that ACR may initiate vicious cycle of modification and aggregation of proteins, including alpha SYN, and impaired proteolysis system, to cause neuronal death in PD.