Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy

Shahnawaz, Mohammad; Mukherjee, Abhisek; Pritzkow, Sandra; Méndez, Natalia; Rabadia, Prakruti; Liu, Xiangan; Hu, Bo; Schmeichel, Ann M.; Singer, Wolfgang; Wu, Gang; Tsai, Alan C.; Shirani, Hamid; Nilsson, K. Peter R.; Low, Phillip A.; Soto, Claudio

doi:10.1038/s41586-020-1984-7

Cited by 512 publications

(556 citation statements)

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“…Recently, studies have aimed at identifying the different α-syn strains between synucleinopathies that could explain their divergent pathologies and clinical manifestations. It has been shown by several teams that there appears to be a specific aggregated form of α-syn that induces PD pathology [13][14][15].α-syn aggregation can be considered as a stochastic event, which would increase with age and/or cell stress conditions, forming initial seed nuclei that would escape cellular clearance due to perturbed proteostasis. Increased α-syn expression and point mutations have been extensively shown to promote aggregation [16].…”

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Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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“…Together with their specific fold, their supramolecular properties also get inherited and propagated as the polymorphs self-replicate by templated growth ( 18-21 ). It is thus tempting to speculate that the distinctive properties of these different polymorphs are causal and bear on the semiology of the different neurodegenerative diseases that are underpinned by a synucleinopathy ( 22-24 ). We noticed, however, that the biological characterization of structurally defined α-syn polymorphs had often been limited to the demonstration of their cellular “toxicity” or “pro-aggregative” action without putting under scrutiny their ability to reproduce their distinctive amyloid fold inside cells.…”

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“…This is also prompting to an accelerated investigation of the possible specific role of stealth α-syn polymorphs in synucleinopathies ( 37 ). Intriguingly, the ThT negativity of α-syn amyloids now appears to repeatedly reconduct to MSA: (i) ribbon amyloids that are ThT-negative ( 12, 18 ) were proposed to recapitulate signs of MSA in injected mice ( 22 ), (ii) fibrils amplified from MSA extracts are barely ThT positive compared to those amplified from Parkinson’s disease ( 24 ), and (iii) we show here that our polymorph 1B (ThT negative) specifically triggers the frequent formation of α-syn inclusions criss-crossing neuronal nuclei. This is reminiscent of the morphology of the Neuronal Nuclear Inclusions that are uniquely seen in MSA and that have been proposed to engage neuronal death ( 38,39 ).…”

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Emergence of stealth polymorphs that escape α-synuclein amyloid monitoring, take over and acutely spread in neurons

Giorgi

Laferrière

Zinghirino

et al. 2020

Preprint

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The conformational strain diversity characterizing α-synuclein (α-syn) amyloid fibrils is possibly at the origin of the different clinical presentations of synucleinopathies. Experimentally, various α-syn fibril polymorphs have been obtained from distinct fibrillization conditions by altering the medium constituents and were selected by amyloid monitoring using the probe Thioflavin T (ThT). We report here that besides classical ThT positive products, fibrillization in saline simultaneously gives rise to competing fibril polymorphs that are invisible to ThT (stealth polymorphs), and that can take over. Due to competition, spontaneous generation of such stealth polymorphs bears on the apparent fibrillization kinetics and on the final plateau values. Their emergence has thus been ignored so far or mistaken for fibrillization inhibitions/failures. Compared to their ThT-positive counterparts, and as judged from their chemical shift resonances fingerprint, these new stealth polymorphs present a yet undescribed atomic organization and show an exacerbated propensity (approx. 20-fold) towards self-replication in cortical neurons. They also trigger a long distance synucleinopathic spread along nigro-striatal projections in vivo. In order to rapidly screen fibrillization products for the presence of such stealth polymorphs, we designed a simple multiplexed assay that can be easily and rapidly operated. This assay allows us to demonstrate the sustainability of the conformational replication of these novel and particularly invasive strains. It should also be of help to avoid erroneous upstream interpretations of fibrillization rates based on sole ThT, and to expedite further structural and functional characterization of stealth amyloid assemblies.One Sentence Summarystealth α-synuclein fibrils take over

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“…Shahnawaz and colleagues used protein misfolding cyclic amplification to discriminate between cerebrospinal fluid α‐synuclein in PD and MSA with a sensitivity of 95.4% . α‐Synuclein was amplified from 169 people with PD and MSA and demonstrated significantly greater fluorescence from PD samples than MSA, suggesting differences in α‐synuclein structure.…”

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Disease‐Specific Strains of α‐Synuclein in Multiple System Atrophy and Parkinson's Disease: But Why?

Fearon

Farrell

2020

Movement Disorders

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Multiple system atrophy (MSA), Parkinson's disease (PD), and dementia with Lewy bodies are naïvely classified together as "the alpha-synucleinopathies." Clinically and pathologically, however, MSA differs from the Lewy body diseases. The unanswered question thus far is the following: why does α-synuclein form neuro-dendritic inclusions in PD and dementia with Lewy bodies but predominantly forms oligodendroglial cytoplasmic inclusions in MSA? The hypothesis that inclusions in PD and MSA comprise different α-synuclein strains that can propagate has been validated in vitro and in murine models. 1 Although oligodendroglial cytoplasmic inclusion-derived strains display more potent seeding and propagation characteristics than Lewy body-derived strains, the precise conformational differences between strains are unclear.Shahnawaz and colleagues used protein misfolding cyclic amplification to discriminate between cerebrospinal fluid α-synuclein in PD and MSA with a sensitivity of 95.4%. 2 α-Synuclein was amplified from 169 people with PD and MSA and demonstrated significantly greater fluorescence from PD samples than MSA, suggesting differences in α-synuclein structure. To confirm these conformational differences, proteinase-K-resistant degradation and differential binding and fluorescence of thiophene-based ligands was used to infer discrepancies in the structural properties of the α-synuclein aggregates. Finally, and most important, the authors employed 2 spectroscopic methods and cryo-electron tomography to show that MSA-derived aggregates have a higher proportion of ß-sheet structure (compared with α-helix/random-coil-type structures in PD). Furthermore, although both strains comprise 2 protofilaments intertwined in a left-hand helix, MSA strains have shorter twists and shorter distances between twists than PD strains.It has, therefore, been shown conclusively that α-synuclein aggregates in PD and MSA comprise different conformational strains that can be discriminated by protein misfolding cyclic amplification. This is an important step both as a diagnostic biomarker and in furthering our understanding of the pathogenesis of these diseases. The question, however, remains the following: why do these conformational differences arise? Oligodendrocytes may pathologically overexpress α-synuclein in MSA 3 but also internalize exogenous α-synuclein from neurons. 4 α-Synuclein is a promiscuous hub protein whose structure alters when interacting with other proteins. 5 Cellular milieu is clearly important. Oligodendrocytes transform Lewy body-derived α-synuclein into a oligodendroglial cytoplasmic inclusionlike strain, and incubating α-synuclein with oligodendrocyte lysate leads to more widespread pathology than with neuronal lysate. 1 One must therefore wonder whether the oligodendroglial environment, which might include other and as yet unidentified synuclein-modifying proteins, is the reason α-synuclein adopts an alternative structure in MSA.A number of novel therapeutic paradigms in MSA are currently being evaluated in clin...

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Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy

Abstract: Reprints and permissions information is available at http://www.nature.com/reprints.

Cited by 512 publications

References 41 publications

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Emergence of stealth polymorphs that escape α-synuclein amyloid monitoring, take over and acutely spread in neurons

Disease‐Specific Strains of α‐Synuclein in Multiple System Atrophy and Parkinson's Disease: But Why?

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