α-Synuclein Amyloid Fibrils with Two Entwined, Asymmetrically Associated Protofibrils

Dearborn, Altaira D.; Wall, Joseph S.; Cheng, Naiqian; Heymann, J. Bernard; Kajava, Andrey V.; Varkey, Jobin; Langen, Ralf; Steven, Alasdair C.

doi:10.1074/jbc.m115.698787

Cited by 51 publications

(54 citation statements)

References 43 publications

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“…The extended monomer conformation leads to an extended and parallel fibril structure. This hypothesis also explains the fact that the low-salt fibrils exhibit no twist, whilst the high-salt fibrils are composed of two entwined twisting protofibrils (as also observed with cryo-electron microscopy83), as both charge84 and size85 are known to influence the twisting properties of protofibrils.…”

Section: Figurementioning

confidence: 53%

Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy

Roeters

Iyer

Pletikapić

et al. 2017

Sci Rep

114

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The aggregation of the intrinsically disordered protein alpha-synuclein (αS) into amyloid fibrils is thought to play a central role in the pathology of Parkinson’s disease. Using a combination of techniques (AFM, UV-CD, XRD, and amide-I 1D- and 2D-IR spectroscopy) we show that the structure of αS fibrils varies as a function of ionic strength: fibrils aggregated in low ionic-strength buffers ([NaCl] ≤ 25 mM) have a significantly different structure than fibrils grown in higher ionic-strength buffers. The observations for fibrils aggregated in low-salt buffers are consistent with an extended conformation of αS molecules, forming hydrogen-bonded intermolecular β-sheets that are loosely packed in a parallel fashion. For fibrils aggregated in high-salt buffers (including those prepared in buffers with a physiological salt concentration) the measurements are consistent with αS molecules in a more tightly-packed, antiparallel intramolecular conformation, and suggest a structure characterized by two twisting stacks of approximately five hydrogen-bonded intermolecular β-sheets each. We find evidence that the high-frequency peak in the amide-I spectrum of αS fibrils involves a normal mode that differs fundamentally from the canonical high-frequency antiparallel β-sheet mode. The high sensitivity of the fibril structure to the ionic strength might form the basis of differences in αS-related pathologies.

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Section: Figurementioning

confidence: 53%

Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy

Roeters

Iyer

Pletikapić

et al. 2017

Sci Rep

114

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“…Taken together, differences in amino acid composition complemented by specific environmental conditions will lead to variations in the stacking and complementation of the intercalating polypeptide backbones of two opposing b-sheet planes. This will result in the formation of individual protofibrils that can form a thin fibril or further assemble with other protofilaments into thick fibrillar assemblies that for example, can be twisted or straight adding a last layer of structural variability (Dearborn et al 2015). Along with these experimental observations, fibrils isolated from the brain of PD and MSA patients showed that these isolated fibrils had differential cylindrical and twisted morphological structures (Spillantini et al 1998b;Crowther et al 2000).…”

Section: The Molecular Origin Of Strainsmentioning

confidence: 76%

“…This will result in the formation of individual protofibrils that can form a thin fibril or further assemble with other protofilaments into thick fibrillar assemblies that for example, can be twisted or straight adding a last layer of structural variability (Dearborn et al . ). Along with these experimental observations, fibrils isolated from the brain of PD and MSA patients showed that these isolated fibrils had differential cylindrical and twisted morphological structures (Spillantini et al .…”

Section: ɑ‐Synuclein Morphometric Variantsmentioning

confidence: 97%

ɑ‐Synuclein strains and the variable pathologies of synucleinopathies

Peelaerts

Baekelandt

2016

Journal of Neurochemistry

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Several decades ago, a mysterious transmissible agent was found responsible for a group of progressive and lethal encephalopathies affecting the nervous system of both animals and humans. This infectious agent showed a strainencoded manner of inheritance even though it lacked nucleic acids. The identification of infectious proteins resolved this apparent conundrum. Misfolded infectious protein particles, or prions, were found to exist as conformational isomers with a unique fingerprint that can be faithfully passaged to next generations. Protein-based strain-encoded inheritance is characterized by strain-specific infectivity and symptomatology. It is found in diverse organisms, such as yeast, fungi, and mammals. Now, this concept is revisited to examine the pathological role of amyloid proteins involved in neurodegenerative diseases where it might underlie certain types of dementia and motor-related neurodegenerative disorders. Given the discovery of the SNCA gene and the identification of its gene product, ɑ-synuclein (ɑ-SYN), as the main histopathological component of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, the scientific community was left puzzled by the fact that a single protein appeared to be involved in different diseases with diverging clinical phenotypes. Recent studies are now indicating that ɑ-SYN may act in a way similar to prions and that ɑ-SYN misfolded structural variants may behave as strains with distinct biochemical and functional properties inducing specific phenotypic traits, which might finally provide an explanation for the clinical heterogeneity observed between Parkinson's disease, MSA, and dementia with Lewy bodies patients. These crucial new findings may pave the way for unexplored therapeutic avenues and identification of new potential biomarkers.

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“…Thus, the H50Q mutation may lower the barrier to nucleation and more readily lead to fibril formation. Previous studies on wild-type α-syn have demonstrated that minor species of single protofilament fibrils exist in polymorphic preparations, suggesting that wildtype a-syn can also form single protofilaments 20 . However, here we observe that single protofilament structures dominate, suggesting that the H50Q mutation may tip the balance to favor single protofilament fibrils and shorter lag times.…”

Section: Discussionmentioning

confidence: 94%

Cryo-EM structures of α-synuclein fibrils with the H50Q hereditary mutation reveal new polymorphs

Boyer

Li²,

Sun³

et al. 2019

Preprint

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Deposits of amyloid fibrils of α-synuclein are the histological hallmarks of Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Although most cases of these diseases are sporadic, autosomal-dominant hereditary mutations have been linked to Parkinson's disease and dementia with Lewy bodies. Seeing the changes to the structure of amyloid fibrils bearing these mutations may help to understand these diseases. To this end, we determined the cryo-EM structures of α-synuclein fibrils containing the H50Q hereditary mutation. We find that the H50Q mutation results in two new polymorphs of α-synuclein, which 2 `we term Narrow and Wide Fibrils. Both polymorphs recapitulate the conserved kernel formed by residues 50-77 observed in wild-type structures; however, the Narrow and Wide Fibrils reveal that H50Q disrupts a key interaction between H50-E57 on the opposing protofilament, abolishing the extensive protofilament interface formed by preNAC residues in the wild-type "rod" structure. Instead, the Narrow Fibril is formed from a single protofilament and the two protofilaments of the Wide protofilament are held together by only a pair of atomsthe Cɣ atoms from the two threonine 59 sidechains. Further, we find that H50Q forms an intramolecular hydrogen bond with K45 leading to the formation of a novel β-arch formed by residues 36-46 that features an extensive hydrogen-bond network between Y39, T44, and E46. The structures of the H50Q polymorphs help to rationalize the faster aggregation kinetics, higher seeding capacity in biosensor cells, and greater cytotoxicity we observe for H50Q compared to wild-type α-synuclein. Introduction:Several lines of evidence suggest that aggregation of α-synuclein (α-syn) into amyloid fibrils underlies the group of diseases termed synucleinopthies -Parkinson's Disease (PD), Lewy Body Dementia (LBD), and Multiple Systems Atrophy (MSA): 1) α-syn fibrils are found in the hallmark lesions of PD and LDB -Lewy Bodiesas well as in the hallmark glial and neuronal lesions in MSA 1,2 . 2) Hereditary mutations in α-syn have been linked to PD and LDB 3 . 3) Dominantly inherited duplications and triplications of the chromosomal region that contains wild-type SNCAthe gene that encodes α-synare sufficient to cause PD 4-6 . 4) Recombinantly assembled α-syn fibrils show cross-β structure and their injection into the brains of wild-type 3 ` mice induced PD-like Lewy body and Lewy neurite formation, as well as cell-to-cell spreading, and motor deficits reminiscent of PD 7,8 .Advances in solid-state NMR and cryo-EM have greatly increased our knowledge of the structure of full-length amyloid proteins, allowing us to examine interactions beyond the local views provided by crystallographic methods 9-13 . Therefore, we previously used cryo-EM to determine the structures of wild-type full-length α-syn fibrils (Figure 1 b, left). These structures reveal two distinct polymorphs -termed the rod and twister 14 . Both fibrils are wound from two identical protofilaments related by an approximate 21 fi...

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α-Synuclein Amyloid Fibrils with Two Entwined, Asymmetrically Associated Protofibrils

Cited by 51 publications

References 43 publications

Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy

Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy

ɑ‐Synuclein strains and the variable pathologies of synucleinopathies

Cryo-EM structures of α-synuclein fibrils with the H50Q hereditary mutation reveal new polymorphs

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