The transgenic overexpression of alpha-synuclein and not its related pathology associates with complex I inhibition.
Alpha-synuclein (alphaS) is a protein involved in the cytopathology and genetics of Parkinson disease and is thought to affect mitochondrial complex I activity. Previous studies have shown that mitochondrial toxins and specifically inhibitors of complex I activity enhance alphaS pathogenesis. Here we show that alphaS overexpression specifically inhibits complex I activity in dopaminergic cells and in A53T alphaS transgenic mouse brains. Importantly, our results indicate that the inhibitory effect on complex I activity is not associated with alphaS-related pathology. Specifically, complex I activity measured in purified mitochondria from A53T alphaS transgenic mouse brains was not affected by mouse age; Parkinson disease-like symptoms; levels of alphaS soluble oligomers; levels of insoluble, lipid-associated alphaS; or alphaS intraneuronal depositions in vivo. Likewise, no correlation was found between complex I activity and polyunsaturated fatty acid-induced alphaS depositions in Lewy body-like inclusions in cultured dopaminergic cells. We further show that the effect of alphaS on complex I activity is not due to altered mitochondrial protein levels or affected complex I assembly. Based on the results herein, we suggest that alphaS expression negatively regulates complex I activity as part of its normal, physiological role.
Loeb
Virginie
V
Department of Biochemistry and Molecular Biology, The Institute for Medical Research, Israel-Canada, Hebrew University, Jerusalem 91120, Israel.
Yakunin
Eugenia
E
Saada
Ann
A
Sharon
Ronit
R
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism*; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D019076:Transgenes; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; D051844:alpha-Synuclein; D042967:Electron Transport Complex I; D004298:Dopamine