Monitoring α-synuclein aggregation

Estaun-Panzano, Juan; Arotcarena, Marie-Laure; Bézard, Erwan

doi:10.1016/j.nbd.2022.105966

Cited by 30 publications

(22 citation statements)

References 220 publications

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“…These findings confirm the structural polymorphism in relation to disease PD/LBD vs. MSA, but it is important, on the other hand, to note that multiple structures found by assembling recombinant α-Syn in vitro did not show similar heterogeneity in the analysis of brain extracted filaments. More results are needed to clarify the extent to which the structure of the fibrils formed in vitro reproduces the structural characteristics of in vivo-formed fibrils, but it appears that the nature of α-Syn filaments is less variable than expected, and similar conclusions are shared by the cryo-EM analysis of other amyloid structures [ 46 , 47 , 48 ].…”

Section: Alpha-synuclein Oligomersmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

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Section: Alpha-synuclein Oligomersmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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“…In typical in vitro tests, the effectiveness of aggregation inhibitors is assessed using a solution containing only αSyn and no other proteins. [66] While they can assess inhibition activity, these tests fail to provide details on the drug's selectivity. For instance, compounds with higher hydrophobic-ity often exhibit greater affinity to αSyn fibrils, because of their interaction with hydrophobic β-sheet rich areas.…”

Section: Problems With Specificitymentioning

confidence: 99%

Navigating α‐Synuclein Aggregation Inhibition: Methods, Mechanisms, and Molecular Targets

Galkin,

Priss,

Kyriukha

et al. 2023

The Chemical Record

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Parkinson's disease is a yet incurable, age‐related neurodegenerative disorder characterized by the aggregation of small neuronal protein α‐synuclein into amyloid fibrils. Inhibition of this process is a prospective strategy for developing a disease‐modifying treatment. We overview here small molecule, peptide, and protein inhibitors of α‐synuclein fibrillization reported to date. Special attention was paid to the specificity of inhibitors and critical analysis of their action mechanisms. Namely, the importance of oxidation of polyphenols and cross‐linking of α‐synuclein into inhibitory dimers was highlighted. We also compared strategies of targeting monomeric, oligomeric, and fibrillar α‐synuclein species, thoroughly discussed the strong and weak sides of different approaches to testing the inhibitors.

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“…Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by a loss of dopaminergic neurons in the substantia nigra of the midbrain region 1 . Additionally, surviving neurons accumulate cytosolic inclusions named Lewy bodies enriched with fibrillar forms of the presynaptic protein α-synuclein (aSyn) 2,3 . Mutations in the gene encoding aSyn have been linked to cases of familial PD 4,5 .…”

Section: Introductionmentioning

confidence: 99%

Protective effects of polyphenol-rich extracts against neurotoxicity elicited by paraquat or rotenone in cellular models of Parkinson’s disease

Tambe

Jacquet

Strathearn

et al. 2023

Preprint

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Parkinson's disease (PD) is a neurodegenerative disorder involving motor symptoms caused by a loss of dopaminergic neurons in the substantia nigra region of the brain. Epidemiological evidence suggests that anthocyanin (ANC) intake is associated with a low risk of PD. Previously, we reported that extracts enriched with ANC and proanthocyanidins (PAC) suppressed dopaminergic neuron death elicited by the PD-related toxin rotenone in a primary midbrain culture model. Here, we characterized botanical extracts enriched with a mixed profile of polyphenols, as well as a set of purified polyphenolic standards, in terms of their ability to mitigate dopaminergic cell death in midbrain cultures exposed to another PD-related toxicant, paraquat (PQ), and we examined underlying neuroprotective mechanisms. Extracts prepared from blueberries, black currants, grape seeds, grape skin, mulberries, and plums, as well as several ANC, were found to rescue dopaminergic neuron loss in PQ-treated cultures. Comparison of a subset of ANC-rich extracts for the ability to mitigate neurotoxicity elicited by PQ versus rotenone revealed that a hibiscus or plum extract was only neuroprotective in cultures exposed to rotenone or PQ, respectively. Several extracts or compounds with the ability to protect against PQ neurotoxicity increased the activity of the antioxidant transcription factor Nrf2 in cultured astrocytes, and PQ-induced dopaminergic cell death was attenuated in Nrf2-expressing midbrain cultures. In other studies, we found that extracts prepared from hibiscus, grape skin, or purple basil (but not plums) rescued defects in O2 consumption in neuronal cells treated with rotenone. Collectively, these findings suggest that extracts enriched with certain combinations of ANC, PAC, stilbenes, and other polyphenols could potentially slow neurodegeneration in the brains of individuals exposed to PQ or rotenone by activating cellular antioxidant mechanisms and/or alleviating mitochondrial dysfunction.

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Monitoring α-synuclein aggregation

Cited by 30 publications

References 220 publications

Alpha Synuclein: Neurodegeneration and Inflammation

Alpha Synuclein: Neurodegeneration and Inflammation

Navigating α‐Synuclein Aggregation Inhibition: Methods, Mechanisms, and Molecular Targets

Protective effects of polyphenol-rich extracts against neurotoxicity elicited by paraquat or rotenone in cellular models of Parkinson’s disease

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