Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways

Almandoz-Gil, Leire; Welander, Hedvig; Ihse, Elisabet; Khoonsari, Payam Emami; Musunuri, Sravani; Lendel, Christofer; Sigvardson, Jessica; Karlsson, Mikael; Ingelsson, Martin; Kultima, Kim; Bergström, Joakim

doi:10.1016/j.freeradbiomed.2017.07.004

Cited by 23 publications

(41 citation statements)

References 49 publications

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“…Although, 4-HNE modifies αSyn immediately, primarily the His50 residue, oligomer formation only occurs with prolonged incubation times (> 24 h) and involving fewer cross-linking events. 4-HNE can bind to αSyn at an acidic pH, but these modifications cannot promote oligomerization even with increased incubation times [ 203 ]. The current objective of research in the field of contribution of 4-HNE-protein adducts is characterization the interactions of 4-HNE with redox sensitive cell signalling proteins.…”

Section: Brain Protein Modifications By 4-hydroxy-23- Tranmentioning

confidence: 99%

Origin and pathophysiology of protein carbonylation, nitration and chlorination in age-related brain diseases and aging

Gonos

Καπετάνου

Sereikaitė

et al. 2018

Aging

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Non-enzymatic protein modifications occur inevitably in all living systems. Products of such modifications accumulate during aging of cells and organisms and may contribute to their age-related functional deterioration. This review presents the formation of irreversible protein modifications such as carbonylation, nitration and chlorination, modifications by 4-hydroxynonenal, removal of modified proteins and accumulation of these protein modifications during aging of humans and model organisms, and their enhanced accumulation in age-related brain diseases.

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Section: Brain Protein Modifications By 4-hydroxy-23- Tranmentioning

confidence: 99%

Origin and pathophysiology of protein carbonylation, nitration and chlorination in age-related brain diseases and aging

Gonos

Καπετάνου

Sereikaitė

et al. 2018

Aging

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“…It is usually found in a soluble, monomeric form, but in pathological conditions, α-syn becomes phosphorylated, aggregated, and, in PD, combined with other proteins like tau to form Lewy bodies (LBs) 18. Inflammation and oxidative stress are proposed to trigger α-syn phosphorylation and aggregation,19–21 thus facilitating the development of PD pathology. LBs are found in the central and peripheral nervous systems of PD patients, including the enteric nervous system (ENS), yet their role in PD neurodegeneration is still unclear.…”

Section: Introductionmentioning

confidence: 99%

<p>Colonic inflammation affects myenteric alpha-synuclein in nonhuman primates</p>

Resnikoff¹,

Metzger²,

Lopez³

et al. 2019

JIR

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Background: Parkinson’s disease (PD) patients frequently present gastrointestinal (GI) dysfunction that, in many cases, predates the onset of motor symptoms. In PD, the presynaptic protein alpha-synuclein (α-syn) undergoes pathological changes, including phosphorylation and aggregation leading to the formation of Lewy bodies, which can be found in neurons of the enteric nervous system (ENS). Inflammation has been proposed as a possible trigger of α-syn pathology. Interestingly, patients with inflammatory bowel disease and irritable bowel syndrome, conditions associated with GI inflammation, are at higher risk of developing PD. Captive common marmosets (Callithrix jacchus) develop colitis, providing a natural platform to assess the relationship between α-syn pathology and GI inflammation. Materials and Methods: Sections of proximal colon from marmosets with colitis (n=5; 5.3±2.3 years old; 4 male) and normal controls (n=5; 4.1±1.6 years old; 1 male) were immunostained against protein gene product 9.5 (PGP9.5), human leukocyte antigen DR (HLA-DR), cluster of differentiation 3 (CD3), cluster of differentiation 20 (CD20), glial fibrillary acidic protein (GFAP), 8-hydroxy-2’-deoxyguanosine (8-OHdG), α-syn, and serine 129 phosphorylated α-syn (p-α-syn). Immunoreactivity of each staining in the myenteric plexus was quantified using NIH ImageJ software. Results: Marmosets with colitis had significantly increased expression of inflammatory markers (HLA-DR, p <0.02; CD3, p <0.008), oxidative stress (8-OHdG, p <0.05), and p-α-syn ( p <0.02) and decreased expression of α-syn ( p <0.04) in the colonic myenteric ganglia compared to normal, healthy controls. Conclusion: Colonic inflammation is associated with changes in α-syn expression and phosphorylation in the myenteric plexus of common marmosets. Future evaluation of the vagus nerve and brain of animals with colitis will be key to assess the contribution of colitis-induced ENS α-syn pathology to PD-like pathology in the brain.

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“…26 – 28 Reactive endogenous small molecules and environmental toxins are known to promote covalent α-synuclein crosslinking, and their potential to nucleate and/or stabilize toxic oligomeric species has sparked recent efforts to define their roles in PD. 2, 14, 29 – 31 …”

Section: Introductionmentioning

confidence: 99%

Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein

et al. 2018

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3,4-dihydroxyphenylacetaldehyde (DOPAL) is a toxic and reactive product of dopamine catabolism. In the catecholaldehyde hypothesis for Parkinson’s disease, it is a critical driver of the selective loss of dopaminergic neurons that characterizes the disease. DOPAL also crosslinks α-synuclein, the main component of Lewy bodies, which are a pathological hallmark of the disease. We previously described the initial adduct formed in reactions between DOPAL and α-synuclein, a dicatechol pyrrole lysine (DCPL). Here, we examine the chemical basis for DOPAL-based crosslinking. We find that autoxidation of DCPL’s catechol rings spurs its decomposition, yielding an intermediate dicatechol isoindole lysine (DCIL) product formed by an intramolecular reaction of the two catechol rings to give an unstable tetracyclic structure. DCIL then reacts with a second DCIL to give a dimeric, di-DCIL. This product is formed by an intermolecular carbon-carbon bond between the isoindole rings of the two DCILs that generates two structurally nonequivalent and separable atropisomers. Using α-synuclein, we demonstrate that the DOPAL-catalyzed formation of oligomers can be separated into two steps. The initial adduct formation occurs robustly within an hour, with DCPL as the main product, and the second step crosslinks α-synuclein molecules. Exploiting this two-stage reaction, we use an isotopic labeling approach to show the predominant crosslinking mechanism is an inter-adduct reaction. Finally, we confirm that a mass consistent with a di-DCIL linkage can be observed in dimeric α-synuclein by mass spectrometry. Our work elucidates previously unknown pathways of catechol-based oxidative protein damage and will facilitate efforts to detect DOPAL-based crosslinks in disease-state neurons.

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Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways

Cited by 23 publications

References 49 publications

Origin and pathophysiology of protein carbonylation, nitration and chlorination in age-related brain diseases and aging

Origin and pathophysiology of protein carbonylation, nitration and chlorination in age-related brain diseases and aging

<p>Colonic inflammation affects myenteric alpha-synuclein in nonhuman primates</p>

Isoindole Linkages Provide a Pathway for DOPAL-Mediated Cross-Linking of α-Synuclein

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