Glycation modulates alpha-synuclein fibrillization kinetics: A sweet spot for inhibition

Farzadfard, Azad; König, Anika; Petersen, Steen V.; Nielsen, Janni; Vasili, Eftychia; Dominguez-Meijide, Antonio; Buell, Alexander K.; Outeiro, Tiago F.; Otzen, Daniel E.

doi:10.1016/j.jbc.2022.101848

Cited by 22 publications

(26 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[18d] However, a more recent study has proved that MG completely inhibits the ability of αS to form oligomers and therefore, to form amyloid fibrils. [28] All these results are complemented by a work of our group where we proved that MG also reduces the protective role of αS against oxidative stress. [29] Here, we have combined a broad set of biophysical techniques to get further insights into the effect of MG on the structure, aggregation propensity and biological function of αS (as a catalyst of the clustering and the fusion of SVs).…”

Section: Introductionmentioning

confidence: 64%

“…Glycation-mediated by MG induces the formation of fluorescent AGEs on αS. [28,32] Accordingly, we observed a temporal increase in the fluorescence emission signal (λ em 410 nm) of αS upon incubation with MG, which is characteristic of the formation of fluorescent AGEs (Figure 2A). They were formed relatively fast, as the fluorescence signal fitted to an exponential rise to a maximum function.…”

Section: Mg Rapidly Induces the Formation Of Fluorescent Ages On αSmentioning

confidence: 74%

See 1 more Smart Citation

Insight into the Effect of Methylglyoxal on the Conformation, Function, and Aggregation Propensity of α‐Synuclein

Mariño,

Belén Uceda,

Leal

et al. 2024

Chemistry A European J

View full text Add to dashboard Cite

It is well‐known that people suffering from hyperglycemia have a higher propensity to develop Parkinson’s disease (PD). One of the most plausible mechanisms linking these two pathologies is the glycation of neuronal proteins and the pathological consequences of it. α‐Synuclein, a key component in PD, can be glycated at its fifteen lysine. In fact, the end products of this process have been detected on aggregated α‐synuclein isolated from in vivo. However, the consequences of glycation are not entirely clear, which are of crucial importance to understand the mechanism underlying the connection between diabetes and PD. To better clarify this, we have here examined how methylglyoxal (the most important carbonyl compound found in the cytoplasm) affects the conformation and aggregation propensity of α‐synuclein, as well as its ability to cluster and fuse synaptic‐like vesicles. The obtained data prove that methylglyoxal induces the Lys‐Lys crosslinking through the formation of MOLD. However, this does not have a remarkable effect on the averaged conformational ensemble of α‐synuclein, although it completely depletes its native propensity to form soluble oligomers and insoluble amyloid fibrils. Moreover, methylglyoxal has a disrupting effect on the ability of α‐synuclein to bind, cluster and fusion synaptic‐like vesicles.

show abstract

Section: Introductionmentioning

confidence: 64%

Section: Mg Rapidly Induces the Formation Of Fluorescent Ages On αSmentioning

confidence: 74%

Insight into the Effect of Methylglyoxal on the Conformation, Function, and Aggregation Propensity of α‐Synuclein

Mariño,

Belén Uceda,

Leal

et al. 2024

Chemistry A European J

View full text Add to dashboard Cite

show abstract

“…97 Glycation and α-Syn fibrillization. 98 3-DG Carbonyl stress; 78 microalbuminuria and T2DM; 99 Glycation and α-Syn 113 entry of pathogens and their metabolites into circulation, accelerating cytokines. 144 The review by Kowalski and…”

Section: Gut Microbesmentioning

confidence: 99%

Communal interaction of glycation and gut microbes in diabetes mellitus, Alzheimer's disease, and Parkinson's disease pathogenesis

Patil,

Tupe

2023

Medicinal Research Reviews

View full text Add to dashboard Cite

Diabetes and its complications, Alzheimer's disease (AD), and Parkinson's disease (PD) are increasing gradually, reflecting a global threat vis‐à‐vis expressing the essentiality of a substantial paradigm shift in research and remedial actions. Protein glycation is influenced by several factors, like time, temperature, pH, metal ions, and the half‐life of the protein. Surprisingly, most proteins associated with metabolic and neurodegenerative disorders are generally long‐lived and hence susceptible to glycation. Remarkably, proteins linked with diabetes, AD, and PD share this characteristic. This modulates protein's structure, aggregation tendency, and toxicity, highlighting renovated attention. Gut microbes and microbial metabolites marked their importance in human health and diseases. Though many scientific shreds of evidence are proposed for possible change and dysbiosis in gut flora in these diseases, very little is known about the mechanisms. Screening and unfolding their functionality in metabolic and neurodegenerative disorders is essential in hunting the gut treasure. Therefore, it is imperative to evaluate the role of glycation as a common link in diabetes and neurodegenerative diseases, which helps to clarify if modulation of nonenzymatic glycation may act as a beneficial therapeutic strategy and gut microbes/metabolites may answer some of the crucial questions. This review briefly emphasizes the common functional attributes of glycation and gut microbes, the possible linkages, and discusses current treatment options and therapeutic challenges.

show abstract

“…In fact, there is evidence that α‐synuclein is glycated in DLB and PD and that glycation reduces α‐synuclein membrane binding and egress from cells 185 . Glycated α‐synuclein monomers are more prone to aggregation, accumulating as oligomeric species, 186 whereas glycated oligomers and fibrils are more resistant to proteasomal and lysosomal degradation 185 . Recently, intracerebroventricular methylglyoxal injection was found to increase glycation of glutamatergic‐associated proteins in midbrain tissue from α‐synuclein transgenic mice, suggesting that glycation also modulates glutamatergic signaling 187 .…”

Section: Shared Pathogenic Mechanisms and Indirect Effectsmentioning

confidence: 99%

Type 2 Diabetes and Parkinson's Disease: A Focused Review of Current Concepts

et al. 2022

Self Cite

View full text Add to dashboard Cite

Highly reproducible epidemiological evidence shows that type 2 diabetes (T2D) increases the risk and rate of progression of Parkinson's disease (PD), and crucially, the repurposing of certain antidiabetic medications for the treatment of PD has shown early promise in clinical trials, suggesting that the effects of T2D on PD pathogenesis may be modifiable. The high prevalence of T2D means that a significant proportion of patients with PD may benefit from personalized antidiabetic treatment approaches that also confer neuroprotective benefits. Therefore, there is an immediate need to better understand the mechanistic relation between these conditions and the specific molecular pathways affected by T2D in the brain. Although there is considerable evidence that processes such as insulin signaling, mitochondrial function, autophagy, and inflammation are involved in the pathogenesis of both PD and T2D, the primary aim of this review is to highlight the evidence showing that T2D‐associated dysregulation of these pathways occurs not only in the periphery but also in the brain and how this may facilitate neurodegeneration in PD. We also discuss the challenges involved in disentangling the complex relationship between T2D, insulin resistance, and PD, as well as important questions for further research. © 2022 International Parkinson and Movement Disorder Society.

show abstract

Glycation modulates alpha-synuclein fibrillization kinetics: A sweet spot for inhibition

Cited by 22 publications

References 86 publications

Insight into the Effect of Methylglyoxal on the Conformation, Function, and Aggregation Propensity of α‐Synuclein

Insight into the Effect of Methylglyoxal on the Conformation, Function, and Aggregation Propensity of α‐Synuclein

Communal interaction of glycation and gut microbes in diabetes mellitus, Alzheimer's disease, and Parkinson's disease pathogenesis

Type 2 Diabetes and Parkinson's Disease: A Focused Review of Current Concepts

Contact Info

Product

Resources

About