α-Synuclein aggregation at low concentrations

Afitska, Kseniia; Fučíková, Anna; Shvadchak, Volodymyr V.

doi:10.1016/j.bbapap.2019.05.003

Cited by 41 publications

(50 citation statements)

References 31 publications

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“…This suggests that fibril seeding is an equilibrium process: adding excessive monomer will promote fibril formation, while continuously removing monomer promotes fibril disaggregation. This idea has been confirmed by fluorescence work, which shows that αS fibrils will disaggregate when the protein concentration is lower than a critical concentration (43).…”

Section: Discussionmentioning

confidence: 74%

NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils

Yang

Wang

Hoop

et al. 2020

Preprint

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Amyloid fibril formation of α-synuclein (αS) is associated with multiple neurodegenerative diseases, including Parkinson's Disease (PD). Growing evidence suggests that progression of PD is linked to cell-to-cell propagation of αS fibrils, which leads to templated seeding of endogenous intrinsically disordered monomer. A molecular understanding of the seeding mechanism and driving interactions is crucial to inhibit progression of amyloid formation. Here, using relaxation-based solution NMR experiments designed to probe large complexes, we identify weak interactions of intrinsically disordered acetylated-αS (Ac-αS) monomers with seeding-competent Ac-αS fibrils and seeding-incompetent off-pathway oligomers to elucidate amyloid promoting interactions at the atomic level. We identify a binding interface in the first 11 residues of the N-terminus that interacts with both fibrils and off-pathway oligomers, under conditions that favor fibril elongation. This common N-terminal hotspot is supported by suppression of seeded amyloid formation by oligomers, as observed through thioflavin-T fluorescence experiments, suggesting competing monomer interactions. This highlights that an amyloid-incompetent species of αS itself can act as an auto-inhibitor against αS fibril elongation. The similarity between the fibril and oligomer structures lies in their intrinsically disordered termini. Thus, we propose that the monomer-aggregate interactions occur between the intrinsically disordered monomer N-terminus and the intrinsically disordered regions (IDRs) of the fibril/oligomers. Taken together, we propose a novel Ac-αS seeding mechanism that is driven by the recruitment of intrinsically disordered monomers by the fibril IDRs, highlighting the potential of the terminal IDRs of the fibril rather than the structured core, as new therapeutic targets against seeded amyloid formation.

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Section: Discussionmentioning

confidence: 74%

NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils

Yang

Wang

Hoop

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…The Majority of Existing Cellular Models Are Models of α-Syn Fibril Formation Rather than LBs. Several in vitro assays (54)(55)(56)(57) and cellular and animal models (9,10,21,22,44,55) of α-syn aggregation and pathology formation have been developed and are commonly used to study these processes. While many of these models reproduce specific aspects or stages of LB pathology formation, none has been shown to form pathological aggregates exhibiting the biochemical and organizational complexity of α-syn pathologies, including LBs, found in postmortem brains of patients with synucleinopathies (5, 13-15, 23, 24, 31, 43, 44).…”

Section: Discussionmentioning

confidence: 99%

The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration

Mahul‐Mellier

Burtscher

Maharjan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

490

551

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Parkinson’s disease (PD) is characterized by the accumulation of misfolded and aggregated α-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LBs). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD, the processes that govern α-syn fibrillization and LB formation remain poorly understood. In this work, we sought to dissect the spatiotemporal events involved in the biogenesis of the LBs at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we further developed a seeding-based model of α-syn fibrillization to generate a neuronal model that reproduces the key events leading to LB formation, including seeding, fibrillization, and the formation of inclusions that recapitulate many of the biochemical, structural, and organizational features of bona fide LBs. Using an integrative omics, biochemical and imaging approach, we dissected the molecular events associated with the different stages of LB formation and their contribution to neuronal dysfunction and degeneration. In addition, we demonstrate that LB formation involves a complex interplay between α-syn fibrillization, posttranslational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria, the autophagosome, and endolysosome. Finally, we show that the process of LB formation, rather than simply fibril formation, is one of the major drivers of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, and synaptic dysfunctions. We believe that this model represents a powerful platform to further investigate the mechanisms of LB formation and clearance and to screen and evaluate therapeutics targeting α-syn aggregation and LB formation.

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“…Several in vitro assays [70][71][72][73] and cellular and animal models 12,17,22,24,71,74 of α-syn aggregation and pathology formation have been developed and are commonly used to study these processes. While many of these models reproduce specific aspects or stages of LB pathology formation, none has been shown to form pathological aggregates exhibiting the biochemical and organizational complexity of α-syn pathologies, including LBs, found in post-mortem brains of patients with synucleinopathies 8,25,26,[29][30][31]39,43,74,75 .…”

Section: Lbsmentioning

confidence: 99%

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

Mahul‐Mellier

Burtscher

Maharjan

et al. 2019

Preprint

View full text Add to dashboard Cite

Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LB). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD and synucleinopathies, the processes that govern α-syn fibrillization and LB formation in the brain remain poorly understood. In this work, we sought to reverse engineer LBs and dissect the spatiotemporal events involved in their biogenesis at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we took advantage of a seeding-based model of α-syn fibril formation in primary neurons and further developed this model to generate the first neuronal model that reproduces the key events leading to LB formation; including seeding, fibrillization, and the formation of LB-like inclusions that recapitulate many of the biochemical, structural, and organizational features of LBs found in post-mortem human PD brain tissues. Next, we applied an integrative approach combining confocal and correlative light-electron microscopy (CLEM) imaging methods with biochemical profiling of α-syn species and temporal proteomic and transcriptomic analyses to dissect the molecular events associated with LB formation and maturation and to elucidate their contributions to neuronal dysfunctions and neurodegeneration in PD and synucleinopathies. The results from these studies demonstrate that LB formation involves a complex interplay between α-syn fibrillization, post-translational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria and the autophagosome and endolysosome. Furthermore, we demonstrate that the process of LB formation and maturation, rather than simply fibril formation, is the major driver of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, as well as synaptic dysfunctions. Having a neuronal model that allows for unlinking of the key processes involved in LB formation is crucial for elucidating the molecular and cellular determinants of each process and their contributions to neuronal dysfunction and degeneration in PD and synucleinopathies. Such a model is essential to efforts to identify and investigate the mode of action and toxicity of drug candidates targeting α-syn aggregation and LB formation.

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α-Synuclein aggregation at low concentrations

Cited by 41 publications

References 31 publications

NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils

NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils

The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

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