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Low molar excess of...
Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways
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- Almandoz-Gil, Leire (författare)
- Uppsala universitet,Geriatrik
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- Welander, Hedvig (författare)
- Uppsala universitet,Geriatrik
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- Ihse, Elisabet, 1977- (författare)
- Uppsala universitet,Geriatrik
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- Khoonsari, Payam Emami (författare)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Musunuri, Sravani (författare)
- Uppsala universitet,Analytisk kemi
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- Lendel, Christofer (författare)
- KTH,Tillämpad fysikalisk kemi,KTH, Royal Institute of Technology, Sweden
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- Sigvardson, Jessica (författare)
- BioArctic AB, Sweden
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- Karlsson, Mikael (författare)
- Uppsala universitet,Tillämpad materialvetenskap
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- Ingelsson, Martin (författare)
- Uppsala universitet,Geriatrik
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- Kultima, Kim (författare)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Bergström, Joakim (författare)
- Uppsala universitet,Geriatrik
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(creator_code:org_t)
- Elsevier BV, 2017
- 2017
- Engelska.
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Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 110, s. 421-431
- Relaterad länk:
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96 h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Nyckelord
- Alpha-synuclein
- Oligomers
- 4-oxo-2-nonenal
- 4-hydroxy-2-nonenal
- Oxidative stress
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- art (ämneskategori)
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Almandoz-Gil, Le ...
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Welander, Hedvig
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Ihse, Elisabet, ...
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Khoonsari, Payam ...
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Musunuri, Sravan ...
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Lendel, Christof ...
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visa fler...
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Sigvardson, Jess ...
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Karlsson, Mikael
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Ingelsson, Marti ...
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Kultima, Kim
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Bergström, Joaki ...
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