In parkinsonian substantia nigra, alpha-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity.
alpha-Synuclein (alphaSYN) plays a central role in the neural degeneration of Parkinson's disease (PD) through its conformational change. In PD, alphaSYN, released from the membrane, accumulates in the cytoplasm and forms Lewy body. However, the mechanism behind the translocation and conformational change of alphaSYN 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, alphaSYN was modified with acrolein (ACR), an aldehyde product of lipid peroxidation. Histopathological observation confirmed the co-localization of protein immunoreactive to anti-alphaSYN and ACR antibody. By Western blot analyses of samples precipitated with either anti-alphaSYN or anti-ACR antibody, increase in ACR-modified alphaSYN was confirmed in PD brain. Modification of recombinant alphaSYN by ACR enhanced its oligomerization, and at higher ACR concentrations alphaSYN 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 alphaSYN, and impaired proteolysis system, to cause neuronal death in PD.
Shamoto-Nagai
M
M
National Center for Geriatrics and Gerontology, Department of Geriatric Medicine, Obu, Aichi, Japan.
Maruyama
W
W
Hashizume
Y
Y
Yoshida
M
M
Osawa
T
T
Riederer
P
P
Naoi
M
M
D000171:Acrolein / Q000378:metabolism*; D000368:Aged; D015153:Blotting, Western; D004298:Dopamine / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D008543:Melanins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*
D008543:Melanins; D051844:alpha-Synuclein; C014121:neuromelanin; D000171:Acrolein; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine
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