Resonance assignments of an α-synuclein fibril prepared in Tris buffer at moderate ionic strength

Barclay, Alexander M.; Dhavale, Dhruva; Courtney, Joseph M.; Kotzbauer, Paul T.; Rienstra, Chad M.

doi:10.1007/s12104-018-9808-5

Cited by 15 publications

(13 citation statements)

References 24 publications

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“…2c, and overlaid it with our αS fibril 13 C- 13 C spectrum; we observe relatively good agreement between the published chemical shifts and our αS spectrum. In addition, we created a 13 C- 13 C chemical shift correlation map using an average of the 13 C chemical shifts from the core residues (44–96) in the 8 human WT entries in the BMRB (Entries: 16939 43 , 17498 44 , 17910 45 , 18243 46 , 18860 44 , 25518 41 , 25535 47 , 26890 48 ) (Fig. 2d).…”

Section: Resultsmentioning

confidence: 99%

“…( b ) Expansion of select regions of the 2D 13 C- 13 C spectra in ( a ) that show the major cross peak intensity differences, which are the Lys, Thr and a tentatively assigned Asn residues. ( c , d ) Overlays of the αS 2D 13 C- 13 C correlation spectrum in ( a ) with chemical shift correlation maps derived from ( c ) the published solid-state NMR structure of αS fibrils (green, PDB: 2N0A, BMRB: 25518 41 ) and ( d ) an average of the 13 C chemical shifts of αS fibrils deposited into the BMRB (BRMB: 16939 43 , 17498 44 , 17910 45 , 18243 46 , 18860 44 , 25518 41 , 25535 47 , 26890 48 ).…”

Section: Resultsmentioning

confidence: 99%

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Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity

Yang

Williams

Yan

et al. 2019

Sci Rep

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Alpha-synuclein (αS) fibrils are toxic to cells and contribute to the pathogenesis and progression of Parkinson’s disease and other synucleinopathies. β-Synuclein (βS), which co-localizes with αS, has been shown to provide a neuroprotective effect, but the molecular mechanism by which this occurs remains elusive. Here we show that αS fibrils formed in the presence of βS are less cytotoxic, exhibit reduced cell seeding capacity and are more resistant to fibril shedding compared to αS fibrils alone. Using solid-state NMR, we found that the overall structure of the core of αS fibrils when co-incubated with βS is minimally perturbed, however, the dynamics of Lys and Thr residues, located primarily in the imperfect KTKEGV repeats of the αS N-terminus, are increased. Our results suggest that amyloid fibril dynamics may play a key role in modulating toxicity and seeding. Thus, enhancing the dynamics of amyloid fibrils may be a strategy for future therapeutic targeting of neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity

Yang

Williams

Yan

et al. 2019

Sci Rep

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“…According to this view, (i) α-Syn amyloid aggregation accidentally originates in a few susceptible neurons [6,21,22], (ii) second to buildup, α-Syn fibril fragments are released or leak out [20], (iii) healthy bystander neurons take up the latter fragments which (iv) seed a new cycle of templated amyloid aggregation [5,6] that eventually kills the cell, causing a new release of fragments, and so on [20]. Different α-Syn fibril strains [15,[23][24][25][26][27][28] could affect the characteristics of every single step [15,29,30]. Thus, just as different prion strains cause different human disease phenotypes [31], distinct α-Syn fibril strains could be at the origin of PD, DLB and MSA [32].…”

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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“…The structure of the fibrillization core of α-syn PFFs generated in phosphate buffer was determined to be an in-register Greek key β-sheet motif containing several stabilizing features including a glutamine latter, an intermolecular salt bridge, several steric zippers, and hydrophobic-core interactions [72]. Using a similar technique, the same group determined that α-syn fibrils prepared in a tris buffer system displayed a remarkably similar structure, with small differences between T44 and V55 as well as the primarily unstructured n-terminus, suggesting this motif as a possible general structure for fibrils [73].…”

Section: The Varied Structures Of α-Synmentioning

confidence: 99%

Transmission of α-synuclein seeds in neurodegenerative disease: recent developments

Karpowicz

Trojanowski

Lee

2019

Laboratory Investigation

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Cell-to-cell transmission of proteopathic alpha-synuclein (α-syn) seeds is increasingly thought to underlie the progression of neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and related synucleinopathies. As such, it is important to understand the chemical and biological relationships between cells and pathological aggregates of α-syn. This brief review updates our understanding of the templated spread of α-syn pathology in neurodegenerative disease from the perspective of proteopathic α-syn seeds, including how these seeds are processed by cells as well as their effects on cellular function. Recent advances in understanding the conformations of α-syn seeds are highlighted, and the possible structural basis for the observed heterogeneity of synucleinopathies is discussed. Finally, we propose the possibility that some known risk factors for synucleinopathies may in fact potentiate the cell-tocell transmission of α-syn pathology via imbalances in interrelated cell biological processes.

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Resonance assignments of an α-synuclein fibril prepared in Tris buffer at moderate ionic strength

Cited by 15 publications

References 24 publications

Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity

Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity

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

Transmission of α-synuclein seeds in neurodegenerative disease: recent developments

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