Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

Miranda, Hugo Vicente; Szegő, Éva M.; Oliveira, Luís M. A.; Breda, Carlo; Darendelioğlu, Ekrem; Oliveira, Rita Machado de; Ferreira, Diana G.; Gomes, Marcos António; Rott, R.; Oliveira, Márcia Santos Duarte de; Munari, Francesca; Enguita, Francisco J.; Simões, Tânia; Rodrigues, Eva Ferreira; Heinrich, Michael; Martins, Ivo C.; Zamolo, Irina; Rieß, Olaf; Cordeiro, Carlos; Ponces-Freire, Ana; Lashuel, Hilal A.; Santos, Nuno C.; Lopes, Luı́sa V.; Xiang, Wei; Jovin, Thomas M.; Penque, Deborah; Engelender, Simone; Zweckstetter, Markus; Klucken, Jochen; Giorgini, Flaviano; Quintas, Alexandre; Outeiro, Tiago F.

doi:10.1093/brain/awx056

Cited by 174 publications

(169 citation statements)

References 91 publications

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“…A recent study has shown that glycation of α-synuclein, a protein whose aggregation is the hallmark of PD, enhanced the aggregation and reduced clearance of toxic oligomers. In vitro and in vivo studies using flies and mice showed that enhanced glycation is toxic while glycation inhibitors reduce aggregation and enhance clearance of α-synuclein, and rescue behavioral phenotypes (Vicente Miranda et al, 2017). Furthermore, these studies also explain the significantly increased risk of PD amongst diabetics.…”

Section: Modeling the Influence Of Ages In Neurodegenerative Diseasesmentioning

confidence: 99%

“…The key finding in the study was that glycation enhanced the aggregation and inhibited clearance of HTT suggesting a direct role of protein glycation in neurodegeneration (Vicente Miranda et al, 2016). In a recent study utilizing flies and mice, it was also shown that accumulation of toxic oligomers due to age-related glycation of α-synuclein resulted in disruption of synaptic transmission in the neurons (Vicente Miranda et al, 2017). …”

Section: Using Invertebrate Models To Study the Impact Of Agesmentioning

confidence: 99%

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The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality

et al. 2018

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Accumulation of advanced glycation end products (AGEs) on nucleotides, lipids, and peptides/proteins are an inevitable component of the aging process in all eukaryotic organisms, including humans. To date, a substantial body of evidence shows that AGEs and their functionally compromised adducts are linked to and perhaps responsible for changes seen during aging and for the development of many age-related morbidities. However, much remains to be learned about the biology of AGE formation, causal nature of these associations, and whether new interventions might be developed that will prevent or reduce the negative impact of AGEs-related damage. To facilitate achieving these latter ends, we show how invertebrate models, notably Drosophila melanogaster and Caenorhabditis elegans, can be used to explore AGE-related pathways in depth and to identify and assess drugs that will mitigate against the detrimental effects of AGE-adduct development.

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Section: Modeling the Influence Of Ages In Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Using Invertebrate Models To Study the Impact Of Agesmentioning

confidence: 99%

The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality

et al. 2018

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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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“…Similarly, in PD, aggregates of the protein α‐synuclein (αS) are found in Lewy bodies3 within neuronal cells. These proteins are often heavily post‐translationally modified, for example, αS undergoes phosphorylation, nitration and truncation,4, 5, 6 this makes it important to be able to characterise the real endogenous aggregates formed in cells, as these can differ from those formed by unmodified proteins.…”

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confidence: 99%

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

et al. 2018

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The aberrant misfolding and subsequent conversion of monomeric protein into amyloid aggregates characterises many neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. These aggregates are highly heterogeneous in structure, generally of low abundance and typically smaller than the diffraction limit of light (≈250 nm). To overcome the challenges these characteristics pose to the study of endogenous aggregates formed in cells, we have developed a method to characterise them at the nanometre scale without the need for a conjugated fluorophore. Using a combination of DNA PAINT and an amyloid‐specific aptamer, we demonstrate that this technique is able to detect and super‐resolve a range of aggregated species, including those formed by α‐synuclein and amyloid‐β. Additionally, this method enables endogenous protein aggregates within cells to be characterised. We found that neuronal cells derived from patients with Parkinson's disease contain a larger number of protein aggregates than those from healthy controls.

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Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

Cited by 174 publications

References 91 publications

The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality

The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality

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

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

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