α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies?

Hoppe, Simon Oliver; Uzunoğlu, Gamze; Nussbaum-Krammer, Carmen

doi:10.3390/biom11070931

Cited by 26 publications

(13 citation statements)

References 145 publications

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“…Therefore, the anatomical origin of the spatial spread, its dynamics, and the affected brain regions have all attracted enormous interest to experimentally identify links between disease progression features and specific α-Syn fibril strains [15,[35][36][37][38][39][40]. For recent reviews see [41,42].…”

Section: Introductionmentioning

confidence: 99%

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

et al. 2022

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The distinct neuropathological features of the different α-Synucleinopathies, as well as the diversity of the α-Synuclein (α-Syn) intracellular inclusion bodies observed in post mortem brain sections, are thought to reflect the strain diversity characterizing invasive α-Syn amyloids. However, this “one strain, one disease” view is still hypothetical, and to date, a possible disease-specific contribution of non-amyloid factors has not been ruled out. In Multiple System Atrophy (MSA), the buildup of α-Syn inclusions in oligodendrocytes seems to result from the terminal storage of α-Syn amyloid aggregates first pre-assembled in neurons. This assembly occurs at the level of neuronal cytoplasmic inclusions, and even earlier, within neuronal intranuclear inclusions (NIIs). Intriguingly, α-Syn NIIs are never observed in α-Synucleinopathies other than MSA, suggesting that these inclusions originate (i) from the unique molecular properties of the α-Syn fibril strains encountered in this disease, or alternatively, (ii) from other factors specifically dysregulated in MSA and driving the intranuclear fibrillization of α-Syn. We report the isolation and structural characterization of a synthetic human α-Syn fibril strain uniquely capable of seeding α-Syn fibrillization inside the nuclear compartment. In primary mouse cortical neurons, this strain provokes the buildup of NIIs with a remarkable morphology reminiscent of cat’s eye marbles (see video abstract). These α-Syn inclusions form giant patterns made of one, two, or three lentiform beams that span the whole intranuclear volume, pushing apart the chromatin. The input fibrils are no longer detectable inside the NIIs, where they become dominated by the aggregation of endogenous α-Syn. In addition to its phosphorylation at S129, α-Syn forming the NIIs acquires an epitope antibody reactivity profile that indicates its organization into fibrils, and is associated with the classical markers of α-Syn pathology p62 and ubiquitin. NIIs are also observed in vivo after intracerebral injection of the fibril strain in mice. Our data thus show that the ability to seed NIIs is a strain property that is integrally encoded in the fibril supramolecular architecture. Upstream alterations of cellular mechanisms are not required. In contrast to the lentiform TDP-43 NIIs, which are observed in certain frontotemporal dementias and which are conditional upon GRN or VCP mutations, our data support the hypothesis that the presence of α-Syn NIIs in MSA is instead purely amyloid-strain-dependent.

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Section: Introductionmentioning

confidence: 99%

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

et al. 2022

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“…In contrast to globular proteins, which usually have just one stable fold [ 15 ], amyloids may have many distinct stably propagating folds, which manifest in different physico-chemical properties and different prion phenotypes, as observed for PrP [ 16 ], Aβ peptide [ 17 ], synuclein [ 18 ], and yeast Sup35 prion [ 19 , 20 , 21 ]. Such structurally and phenotypically different prions are referred to as «strains» in mammalian PrP studies and as «variants» in the case of yeast prions, to avoid confusion with strains of yeast.…”

Section: Amyloids and Prions—a General Descriptionmentioning

confidence: 99%

Structural Bases of Prion Variation in Yeast

Kushnirov

Dergalev

Alieva

et al. 2022

IJMS

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Amyloids are protein aggregates with a specific filamentous structure that are related to a number of human diseases, and also to some important physiological processes in animals and other kingdoms of life. Amyloids in yeast can stably propagate as heritable units, prions. Yeast prions are of interest both on their own and as a model for amyloids and prions in general. In this review, we consider the structure of yeast prions and its variation, how such structures determine the balance of aggregated and soluble prion protein through interaction with chaperones and how the aggregated state affects the non-prion functions of these proteins.

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“…These different pathologies may be due to the fact that α-Syn forms conformationally distinct amyloid assemblies (Bousset et al, 2013; Hoppe et al, 2021; Shahnawaz et al, 2020; Strohäker et al, 2019; Van der Perren et al, 2020). Indeed, distinct α-Syn polymorphs have been shown to differ in their aggregation and propagation propensities and levels of toxicity in vivo (Bousset et al, 2013; Hoppe et al, 2021; Van der Perren et al, 2020). Moreover, the cellular environment seems to play a crucial role (Peng et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Dissecting aggregation and seeding dynamics of α-Syn polymorphs using the phasor approach to FLIM

Tittelmeier

Druffel-Augustin

Alik

et al. 2022

Preprint

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Synucleinopathies are a heterogenous group of neurodegenerative diseases characterized by the progressive accumulation of pathological α-synuclein (α-Syn). The importance of the structural polymorphism of α-Syn assemblies for distinct synucleinopathies and their progression is increasingly recognized. However, the underlying mechanisms are poorly understood. Here we use fluorescence lifetime imaging microscopy (FLIM) to investigate seeded aggregation of α-Syn in a biosensor cell line. We show that conformationally distinct α-Syn polymorphs exhibit characteristic fluorescence lifetimes. FLIM further revealed that α-Syn polymorphs were differentially processed by cellular clearance pathways, yielding fibrillar species with increased seeding capacity. Thus, FLIM is not only a powerful tool to distinguish different amyloid structures, but also to monitor the dynamic process of amyloid remodeling by the cellular environment. Our data suggest that the accumulation of highly seeding competent degradation products for particular polymorphs may account for accelerated disease progression in some patients.

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α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies?

Cited by 26 publications

References 145 publications

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

Structural Bases of Prion Variation in Yeast

Dissecting aggregation and seeding dynamics of α-Syn polymorphs using the phasor approach to FLIM

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