Peroxidase mechanism of lipid-dependent cross-linking of synuclein with cytochrome C: protection against apoptosis versus delayed oxidative stress in Parkinson disease.
Damage of presynaptic mitochondria could result in release of proapoptotic factors that threaten the integrity of the entire neuron. We discovered that alpha-synuclein (Syn) forms a triple complex with anionic lipids (such as cardiolipin) and cytochrome c, which exerts a peroxidase activity. The latter catalyzes covalent hetero-oligomerization of Syn with cytochrome c into high molecular weight aggregates. Syn is a preferred substrate of this reaction and is oxidized more readily than cardiolipin, dopamine, and other phenolic substrates. Co-localization of Syn with cytochrome c was detected in aggregates formed upon proapoptotic stimulation of SH-SY5Y and HeLa cells and in dopaminergic substantia nigra neurons of rotenone-treated rats. Syn-cardiolipin exerted protection against cytochrome c-induced caspase-3 activation in a cell-free system, particularly in the presence of H(2)O(2). Direct delivery of Syn into mouse embryonic cells conferred resistance to proapoptotic caspase-3 activation. Conversely, small interfering RNA depletion of Syn in HeLa cells made them more sensitive to dopamine-induced apoptosis. In human Parkinson disease substantia nigra neurons, two-thirds of co-localized Syn-cytochrome c complexes occurred in Lewy neurites. Taken together, these results indicate that Syn may prevent execution of apoptosis in neurons through covalent hetero-oligomerization of cytochrome c. This immediate protective function of Syn is associated with the formation of the peroxidase complex representing a source of oxidative stress and postponed damage.
Bayir
Hülya
H
Center for Free Radical and Antioxidant Health, Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania 15219-3130, USA. bayihx@ccm.upmc.edu
Kapralov
Alexandr A
AA
Jiang
Janfei
J
Huang
Zhentai
Z
Tyurina
Yulia Y
YY
Tyurin
Vladimir A
VA
Zhao
Qing
Q
Belikova
Natalia A
NA
Vlasova
Irina I
II
Maeda
Akihiro
A
Zhu
Jianhui
J
Na
Hye-Mee
HM
Mastroberardino
Pier-Giorgio
PG
Sparvero
Louis J
LJ
Amoscato
Andrew A
AA
Chu
Charleen T
CT
Greenamyre
John T
JT
Kagan
Valerian E
VE
D000818:Animals; D017209:Apoptosis; D002308:Cardiolipins / Q000502:physiology; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003432:Cross-Linking Reagents; D045304:Cytochromes c / Q000378:metabolism*; D006367:HeLa Cells / Q000502:physiology; D006801:Humans; D008055:Lipids / Q000502:physiology; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000502:physiology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000201:enzymology / Q000503:physiopathology*; D010544:Peroxidases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051843:Synucleins / Q000235:genetics / Q000378:metabolism*
D002308:Cardiolipins; D003432:Cross-Linking Reagents; D008055:Lipids; D034741:RNA, Small Interfering; D051843:Synucleins; D045304:Cytochromes c; D010544:Peroxidases