Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro.
The precursor of non-amyloid beta protein component of Alzheimer's disease amyloid (NACP/alpha-synuclein), found in Lewy bodies of Parkinson's disease (PD), is a presynaptic protein genetically linked to some familial types PD. Mechanisms of abnormal NACP/alpha-synuclein aggregation in neurodegenerative diseases are unclear. Since oxidative stress might play a role in PD pathogenesis, we investigated the role of iron and peroxide in NACP/alpha-synuclein aggregation. Immunoblot analysis showed that human NACP/alpha-synuclein (but not beta-synuclein) aggregated in the presence of ferric ion and was inhibited by the iron chelator deferoxamine. Ferrous ion was not effective by itself, but it potentially aggregated NACP/alpha-synuclein in the presence of hydrogen peroxide. NACP/ alpha-synuclein aggregates displayed strong thioflavine-S and congo-red reactivity, reminiscent of amyloid. This study suggests that NACP/alpha-synuclein aggregation might be closely related to oxidative reactions which may play a critical role in neurodegeneration in disorders with Lewy bodies.
Hashimoto
M
M
Department of Neurosciences, University of California San Diego, La Jolla 92093-0624, USA.
Hsu
L J
LJ
Xia
Y
Y
Takeda
A
A
Sisk
A
A
Sundsmo
M
M
Masliah
E
E
D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry* / Q000187:drug effects / Q000648:ultrastructure; D002384:Catalysis; D002712:Chlorides; D005290:Ferric Compounds / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000187:drug effects / Q000648:ultrastructure; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein
D000682:Amyloid; D002712:Chlorides; D005290:Ferric Compounds; D005296:Ferrous Compounds; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; C497607:SNCB protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; C029451:ferrous chloride; C024555:ferric chloride