Evidence of distinct α-synuclein strains underlying disease heterogeneity

Holec, Sara A. M.; Woerman, Amanda L.

doi:10.1007/s00401-020-02163-5

Cited by 68 publications

(62 citation statements)

References 108 publications

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“…These ordered aggregates of α-syn serve as a precursor in Lewy body formation, which is a hallmark of several neurodegenerative diseases (e.g. Parkinson's disease (PD), PD dementia, dementia with Lewy bodies, and multiple system atrophy) [7][8][9][10][11] . The different roles of α-syn in normal synaptic activity and as a factor in the advancement of PD may stem from different manifestations of its structure.…”

mentioning

confidence: 99%

The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

Chen

Zaer

Drori

et al. 2020

Preprint

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The intrinsically disordered protein, α-synuclein, implicated in synaptic vesicle homeostasis and neurotransmitter release, is also associated with several neurodegenerative diseases. The different roles of α-synuclein are characterized by distinct structural states (membrane-bound, dimer, tetramer, oligomer, and fibril), which are originated from its various monomeric conformations. The pathological states, determined by the ensemble of α-synuclein monomer conformations and dynamic pathways of interconversion between dominant states, remain elusive due to their transient nature. Here, we use inter-dye distance distributions from bulk time-resolved Förster resonance energy transfer as restraints in discrete molecular dynamics simulations to map the conformational space of the α-synuclein monomer. We further confirm the generated conformational ensemble in orthogonal experiments utilizing far-UV circular dichroism and cross-linking mass spectrometry. Single-molecule protein-induced fluorescence enhancement measurements show that within this conformational ensemble, some of the conformations of α-synuclein are surprisingly stable, exhibiting conformational transitions slower than milliseconds. Our comprehensive analysis of the conformational ensemble reveals essential structural properties and potential conformations that promote its various functions in membrane interaction or oligomer and fibril formation.

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mentioning

confidence: 99%

The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

Chen

Zaer

Drori

et al. 2020

Preprint

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“…Possible differences in molecular species of αS may account for phenotypic differences between Parkinson disease (PD) and multiple system atrophy (MSA), while molecular determinants in αS that distinguish PD and MSA remain to be clarified. 10 In the AD brain, gradual transition from four-repeat (4R) tau in pretangle to three-repeat (3R) tau in ghost tangle is consistent. Because this profile shift occurs along with regional spread of AD-NFT, it is considered to be a fundamental phenomenon underpinning AD pathogenesis, as discussed by Uchihara.…”

mentioning

confidence: 86%

Reconsidering the Braak–prion hypothesis: truths or realities

2020

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“…Akin to prion diseases and tauopathies, synucleinopathies are believed to harbor distinct strains of α-synuclein that give rise to unique disease phenotypes [ 4 , 5 , 14 , 65 , 66 ]. Indeed, several α-synuclein strains isolated from humans with synucleinopathies were transmitted to transgenic mice and produced unique disease phenotypes [ 4 , 5 , 65 ].…”

Section: Synucleinopathiesmentioning

confidence: 99%

From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases

Baskakov

2021

IJMS

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A number of neurodegenerative diseases including prion diseases, tauopathies and synucleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformationally distinct, self-replicating states referred to as strains. Structural diversity of strains formed by tau, α-synuclein or prion proteins has been well documented. However, the question how different strains formed by the same protein elicit different clinical phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that posttranslational modifications are important players in defining strain-specific structures and disease phenotypes. This article put forward a new hypothesis referred to as substrate selection hypothesis, according to which individual strains selectively recruit protein isoforms with a subset of posttranslational modifications that fit into strain-specific structures. Moreover, it is proposed that as a result of selective recruitment, strain-specific patterns of posttranslational modifications are formed, giving rise to unique disease phenotypes. Future studies should define whether cell-, region- and age-specific differences in metabolism of posttranslational modifications play a causative role in dictating strain identity and structural diversity of strains of sporadic origin.

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Evidence of distinct α-synuclein strains underlying disease heterogeneity

Cited by 68 publications

References 108 publications

The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

Reconsidering the Braak–prion hypothesis: truths or realities

From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases

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