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- Fagerqvist, Therese, et al.
(author)
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Off-pathway alpha-synuclein oligomers seem to alter alpha-synuclein turnover in a cell model but lack seeding capability in vivo
- 2013
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In: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 20:4, s. 233-244
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Journal article (peer-reviewed)abstract
- Aggregated α-synuclein is the major component of Lewy bodies, protein inclusions observed in the brain in neurodegenerative disorders such as Parkinson’s disease and dementia with Lewy bodies. Experimental evidence indicates that α-synuclein potentially can be transferred between cells and act as a seed to accelerate the aggregation process. Here, we investigated in vitro and in vivo seeding effects of α-synuclein oligomers induced by the reactive aldehyde 4-oxo-2-nonenal (ONE). As measured by a Thioflavin-T based fibrillization assay, there was an earlier onset of aggregation when α-synuclein oligomers were added to monomeric α-synuclein. In contrast, exogenously added α-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing α-synuclein that were treated with the oligomers displayed reduced α-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected α-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of α-synuclein oligomers into the neocortex of α-synuclein transgenic mice did not induce formation of Proteinase K resistant α-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced α-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model.
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| 3. |
- Oliw, Ernst H., 1948-, et al.
(author)
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Manganese lipoxygenase oxidizes bis-allylic hydroperoxides and octadecenoic acids by different mechanisms
- 2011
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In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1811:3, s. 138-147
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Journal article (peer-reviewed)abstract
- Manganese lipoxygenase (MnLOX) oxidizes (11R)-hydroperoxylinolenic acid (11R-HpOTrE) to a peroxyl radical. Our aim was to compare the enzymatic oxidation of 11R-HpOTrE and octadecenoic acids with LOO-H and allylic C-H bond dissociation enthalpies of ~88 and ~87kcal/mol. Mn(III)LOX oxidized (11Z)-, (12Z)-, and (13Z)-18:1 to hydroperoxides with R configuration, but this occurred at insignificant rates (<1%) compared to 11R-HpOTrE. We next examined whether transitional metals could mimic this oxidation. Ce(4+) and Mn(3+) transformed 11R-HpOTrE to hydroperoxides at C-9 and C-13 via oxidation to a peroxyl radical at C-11, whereas Fe(3+) was a poor catalyst. Our results suggest that MnLOX oxidizes bis-allylic hydroperoxides to peroxyl radicals in analogy with Ce(4+) and Mn(3+). The enzymatic oxidation likely occurs by proton-coupled electron transfer of the electron from the hydroperoxide anion to Mn(III) and H(+) to the catalytic base, Mn(III)OH(-). Hydroperoxides abolish the kinetic lag times of MnLOX and FeLOX by oxidation of their metal centers, but 11R-HpOTrE was isomerized by MnLOX to (13R)-hydroperoxy-(9Z,11E,15Z)-octadecatrienoic acid (13R-HpOTrE) with a kinetic lag time. This lag time could be explained by two competing transformations, dehydration of 11R-HpOTrE to 11-ketolinolenic acid and oxidation of 11R-HpOTrE to peroxyl radical; the reaction rate then increases as 13R-HpOTrE oxidizes MnLOX with subsequent formation of two epoxyalcohols. We conclude that oxidation of octadecenoic acids and bis-allylic hydroperoxides occurs by different mechanisms, which likely reflect the nature of the hydrogen bonds, steric factors, and the redox potential of the Mn(III) center.
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| 4. |
- Valham, Fredrik, 1972-, et al.
(author)
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Ambient temperature and obstructive sleep apnea : effects on sleep, sleep apnea and morning alertness
- 2012
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In: Sleep. - Westchester : American Academy of Sleep Medicine. - 0161-8105 .- 1550-9109. ; 35:4, s. 513-517
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Journal article (peer-reviewed)abstract
- Study Objectives: The aim of the study was to investigate the effect of ambient temperature on sleep, sleep apnea, and morning alertness in patients with obstructive sleep apnea. Design: Randomized controlled trial. Setting: In-hospital investigations. Participants: Forty patients with obstructive sleep apnea naive to treatment, with an apnea-hypopnea index of 10-30. Interventions: Three different nights in room temperatures of 16 degrees C, 20 degrees C, and 24 degrees C. Measurements: Overnight polysomnography and Karolinska Sleepiness Scale. Results: The obstructive apnea-hypopnea index was 30 +/- 17 at 16 degrees C room temperature, 28 +/- 17 at 20 degrees C, and 24 +/- 18 at 24 degrees C. The obstructive apnea-hypopnea index was higher at 16 degrees C room temperature versus 24 degrees C (P = 0.001) and at 20 degrees C room temperature versus 24 degrees C (P = 0.033). Total sleep time was a mean of 30 min longer (P = 0.009), mean sleep efficiency was higher (77 +/- 11% versus 71 +/- 13% respectively, P = 0.012), and the patients were significantly more alert according to the Karolinska Sleepiness Scale (P < 0.028) in the morning at 16 degrees C room temperature versus 24 degrees C. The amount of sleep in different sleep stages was not affected by room temperature. Conclusions: Untreated patients with obstructive sleep apnea sleep longer, have better sleep efficiency, and are more alert in the morning after a night's sleep at 16 degrees C room temperature compared with 24 degrees C, but obstructive sleep apnea is more severe at 16 degrees C and 20 degrees C compared with 24 degrees C.
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