<i>In vitro</i> models of synucleinopathies: informing on molecular mechanisms and protective strategies

Marvian, Amir Tayaranian; Koss, David J.; Aliakbari, Farhang; Morshedi, Dina; Outeiro, Tiago F.

doi:10.1111/jnc.14707

Cited by 26 publications

(22 citation statements)

References 328 publications

(459 reference statements)

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“…In order to assess whether Hsp27 modulated the MGO‐induced aggregation of aSyn, we used an established cell model using an aggregation‐prone variant of aSyn (known as SynT) 19,64,66‐68 . This model consists of a modified form of aSyn where the C‐terminus is fused to a truncated, nonfluorescent fragment of GFP (known as SynT) 36,69 .…”

Section: Resultsmentioning

confidence: 99%

Hsp27 reduces glycation‐induced toxicity and aggregation of alpha‐synuclein

et al. 2020

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract α-synuclein (aSyn) is a major player in Parkinson's disease and a group of other disorders collectively known as synucleinopathies, but the precise molecular mechanisms involved are still unclear. aSyn, as virtually all proteins, undergoes a series of posttranslational modifications during its lifetime, which can affect its biology and pathobiology. We recently showed that glycation of aSyn by methylglyoxal (MGO) potentiates its oligomerization and toxicity, induces dopaminergic neuronal cell loss in mice, and affects motor performance in flies. Small heat-shock proteins (sHsps) are molecular chaperones that facilitate the folding of proteins or target misfolded proteins for clearance. Importantly, sHsps were shown to prevent aSyn aggregation and cytotoxicity.Upon treating cells with increasing amounts of methylglyoxal, we found that the levels of Hsp27 decreased in a dose-dependent manner. Therefore, we hypothesized that restoring the levels of Hsp27 in glycating environments could alleviate the pathogenicity of aSyn. Consistently, we found that Hsp27 reduced MGO-induced aSyn aggregation in cells, leading to the formation of nontoxic aSyn species. Remarkably, increasing the levels of Hsp27 suppressed the deleterious effects induced by MGO. Our findings suggest that in glycating environments, the levels of Hsp27 are important for modulating the glycation-associated cellular pathologies in synucleinopathies.

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Section: Resultsmentioning

confidence: 99%

Hsp27 reduces glycation‐induced toxicity and aggregation of alpha‐synuclein

et al. 2020

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“…The largest affinity of ZPD-2 for early aggregating species is also inferred from the fact that it mainly impacts the nucleation constant, reducing it by threefold. This might also explain why, at a 0.7:1 ratio, the molecule works well for the A30P (96% inhibition) and H50Q (94% inhibition) familial variants, provided that both mutations facilitate oligomerization, H50Q favoring also fibrillation (Marvian et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

ZPD-2, a Small Compound That Inhibits α-Synuclein Amyloid Aggregation and Its Seeded Polymerization

Peña-Díaz

Pujols

Conde-Giménez

et al. 2019

Front. Mol. Neurosci.

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α-Synuclein (α-Syn) forms toxic intracellular protein inclusions and transmissible amyloid structures in Parkinson's disease (PD). Preventing α-Syn self-assembly has become one of the most promising approaches in the search for disease-modifying treatments for this neurodegenerative disorder. Here, we describe the capacity of a small molecule (ZPD-2), identified after a high-throughput screening, to inhibit α-Syn aggregation. ZPD-2 inhibits the aggregation of wild-type α-Syn and the A30P and H50Q familial variants in vitro at substoichiometric compound:protein ratios. In addition, the molecule prevents the spreading of α-Syn seeds in protein misfolding cyclic amplification assays. ZPD-2 is active against different α-Syn strains and blocks their seeded polymerization. Treating with ZPD-2 two different PD Caenorhabditis elegans models that express α-Syn either in muscle or in dopaminergic (DA) neurons substantially reduces the number of α-Syn inclusions and decreases synuclein-induced DA neurons degeneration. Overall, ZPD-2 is a hit compound worth to be explored in order to develop lead molecules for therapeutic intervention in PD.

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“…The available cellular models range from powerful yeast cells, to neuronal and non‐neuronal mammalian cell lines (human and non‐human), primary neuronal cultures and, more recently, patient‐derived iPS cells, to name just a few (Delenclos et al, ; Marvian, Koss, Aliakbari, Morshedi, & Outeiro, ). Different aSyn expression systems have also been employed, enabling transient or stable expression of either wild‐type or PD‐associated mutant forms of aSyn (Delenclos et al, ; Lazaro, Pavlou, & Outeiro, ; Vasili, Dominguez‐Meijide, & Outeiro, ).…”

Section: Cell Models Of Asyn Toxicity and Aggregationmentioning

confidence: 99%

Synucleinopathies: Where we are and where we need to go

Brás

Dominguez-Meijide

Gerhardt

et al. 2020

Journal of Neurochemistry

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All authors contributed equally to this manuscript. This artic le is relat ed to the Speci al Issue "Synuc lein" Abbreviations: A30P, aSyn substitution of an alanine for a proline at position 30; A53E, aSyn substitution of an alanine for a glutamic acid at position 53; A53T, aSyn substitution of an alanine for a tyrosine at position 53; ALP, autophagy-lysosomal pathway; APLP1, Aβ precursor-like protein 1; aSyn, alpha-synuclein; BiFC, bimolecular fluorescence complementation; CMA, Chaperone-mediated autophagy; CNS, central nervous system; co-IP, co-immunoprecipitation; Cryo-EM, cryo-electron microscopy; CSF, cerebrospinal fluid; Cu, copper; DLB, dementia with Lewy bodies; E46K, aSyn substitution of a glutamic acid for a lysine at position 46; ENS, enteric nervous system; ER, endoplasmic reticulum; Fe, iron; FRET, fluorescence resonance energy transfer; G51D, aSyn substitution of a glycine for a aspartic acid at position 51Abstract Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019:Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.

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In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

Cited by 26 publications

References 328 publications

Hsp27 reduces glycation‐induced toxicity and aggregation of alpha‐synuclein

Hsp27 reduces glycation‐induced toxicity and aggregation of alpha‐synuclein

ZPD-2, a Small Compound That Inhibits α-Synuclein Amyloid Aggregation and Its Seeded Polymerization

Synucleinopathies: Where we are and where we need to go

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