Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 378, Issue 2, Pages 269-277Publisher
ACADEMIC PRESS INC
DOI: 10.1006/abbi.2000.1822
Keywords
alpha-synuclein; copper; metal-catalyzed oxidation; self-oligomerization; protein aggregation; neurodegenerative disease
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alpha-Synuclein is a component of abnormal protein depositions of Lewy bodies and senile plaques found in Parkinson's and Alzheimer's diseases, respectively, By using chemical coupling reagents such as dicyclohexylcarbodiimide or N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline, the protein was shown to experience self-oligomerization in the presence of either copper(II) or A beta 25-35, The oligomers which appeared as a ladder on a 10-20% Tricine/SDS-PAGE have been suggested to participate in the formation of protein aggregations by possibly providing a nucleation center, Since oxidatively modified protein could increase its own tendency toward protein aggregation, metal-catalyzed oxidation of alpha-synuclein has been examined with copper(II) and hydrogen peroxide in the absence of the coupling reagent, intriguingly, the protein was also self-oligomerized into an SDS-resistant ladder on the gel. This biochemically specific copper-mediated oxidative oligomerization was shown to be dependent upon the acidic C-terminus of alpha-synuclein because the C-terminally truncated proteins such as alpha-syn114 and alpha-syn97 were not affected by the metal and hydrogen peroxide, More importantly, the oxidative oligomerization was synergistically enhanced by the presence of A beta 25-35, indicating that the peptide interaction with alpha-synuclein facilitated the copper(II) binding to the acidic C-terminus and subsequent oxidative crosslinking, It has been, therefore, suggested that abnormalities in copper and H2O2 homeostasis and certain pathological factors functionally similar to the A beta 25-35 could play critical roles in the metal-catalyzed oxidative oligomerization of alpha-synuclein, which may lead to possible protein aggregation and neurodegenerations, (C) 2000 Academic Press.
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